Atopic Dermatitis (AD) is a widespread condition which affects approximately 223 million patients globally per year, with 43 million of those affected being children between the ages of 1 and 4¹. AD can severely affect the quality of life, yet for many years treatment has been focused on topical corticosteroids with few advancements being made. Recently, however, several developments have been observed which could shift the treatment to having fewer side effects or offering patients more treatment choice if one option is inadequate. This article discusses some new developments in the topical treatment of Atopic Dermatitis and what this could mean for the quality of life for these patients.

What is Atopic Dermatitis?

Atopic dermatitis (AD) affects up to 10% of adults and 20% of children. Globally, it ranks 15th among non-fatal diseases in terms of disease burden and is the leading skin condition. Common symptoms during flare-ups include dry, itchy, inflamed, and cracked skin.

The causes of AD have not been fully mapped. Experts currently attribute its incidence to a combination of genetic factors and environmental influences. Genetics are believed to play a significant role with 30% of people with AD having a genetic mutation which decreases the protein Filaggrin, resulting in a weaker dermis. Other mutations which disrupt collagen and linoleic acid production are also being studied as relevant for the development of AD. These disruptions allow allergens to penetrate the skin, leading to inflammation. While AD is non-communicable, patients with AD have a widespread colonisation of the bacterium Staphylococcus aureus, which is known to cause skin infections. Additionally, AD has been observed to have a higher prevalence in industrialised countries as well as cold and dry climates. Nevertheless, a clear causal path for AD has not yet been established.

AD usually appears for the first time in childhood and can affect child development. It forms part of the “atopic triad” where children with Atopic Dermatitis are also more likely to develop allergies and asthma, and vice versa. The symptoms can progress as patients age, often resulting in psychological side effects such as social anxiety.

The Gold Standard: Corticosteroids, Calcineurin Inhibitors and their side effects

The main treatments for Atopic Dermatitis are currently Corticosteroids and Calcineurin Inhibitors. Corticosteroids are a group of steroid hormones that affect the body’s immune response. Calcineurin Inhibitors are a class of immunosuppressants, that can be used to manage autoimmune disease. Both are known to be effective at treating AD in their topical formulations and have for a long time been the only treatments available.

Despite being the first line treatments, Corticosteroids and Calcineurin Inhibitors come with significant side effects. Corticosteroids can cause skin atrophy, stretch marks, changes in skin pigmentation and could increase the risk of skin infections. Both Corticosteroids and Calcineurin inhibitors have been linked to an increased risk of cancer. Given the prevalence of the condition in children, the side effects are real concerns for parents.

Enhancing existing solutions: Corticosteroids

In the past few years new topical (and systemic) options have been slowly entering the market, some of which are currently only officially approved for other skin conditions but show potential for AD. However, the main goal of these new treatments, is not to be more effective than Corticosteroids, but mainly to have less potential side effects than existing topical treatments.

A new solution with a Corticosteroid composition is currently going through clinical trials. SNG100 (Seanergy Dermatology Ltd.) is formulated as a topical cream containing 1% hydrocortisone. Its unique formulation contains Sulphated Polysaccharide which acts to hydrate, moisturise and repair the skin barrier, while the hydrocortisone acts as an anti-inflammatory. In a phase I, double-blind, randomised trial², SNG100 was tested on 60 patients over the age of 6, following which, patient severity of AD reduced more significantly than for those who were treated with comparable options (such as only hydrocortisone). Patients treated with SNG100 showed good tolerability and more lasting results, although a higher sample will be required to show more significant effects.

Modulating the Immune Response: Janus Kinase (JAK) Inhibitors

Janus Kinase (JAK) inhibitors are another category of treatment used for AD. JAK inhibitors are immune-modulating treatments, given both topically and systemically. They target the enzymes of the Janus Kinase family, which are important signalling pathways of various cytokines, growth factors, and hormones, however when dysregulated this signalling can enhance diseases such as autoimmune conditions. Consequently, JAK inhibitors can block the signalling pathways involved in AD, thereby reducing the associated inflammation.

Since 2001, only one topical molecular treatment for inflammatory skin disease has been approved by the FDA. In September 2021 Ruxolitinib (sold under brand Opzelura, Incyte Corporation), became the first topical JAK inhibitor approved for AD. It had previously been approved for cancer treatment only. The approval was only for patients with AD over the age of 12. In 2023, a phase IIb, double-blind, randomised, vehicle-controlled trial was conducted indicating that Ruxolitinib was safe for children³, increasing the possibilities of treatment for a larger patient population.

At the same time, there is another JAK inhibitor on the horizon currently being tested through phase II trials⁴. JAK inhibitors are known to have systemic exposure (affecting the body overall not only one targeted part), which can be a concern for children due to the extent of side effects. ATI-1777 (Aclaris Therapeutics) is a new JAK inhibitor which is delivered as a spray-on solution, designed to minimise systemic exposure and thereby lessen risks and side effects.

In the phase IIb trial, 250 patients aged 12 and older with mild to moderate atopic dermatitis were randomly assigned to different concentrations of ATI-1777 or a placebo. The trial showed that ATI-1777 was effective, particularly the 2% concentration applied twice daily, which significantly improved eczema severity scores by 69.7% compared to 58.7% in the placebo group. Importantly, no common side effects seen with other JAK inhibitors, like infections or heart issues, were observed in this study.

JAK inhibitors represent a promising advancement in the treatment of AD, with new therapies like ATI-1777 showing significant efficacy while minimising systemic side effects. As more options progress through clinical trials, they could offer safer and more effective treatment alternatives, particularly for younger patients and those concerned about the broader impacts of systemic exposure.

Targeting Enzymes: Phosphodiesterase-4 Inhibitors

Phosphodiesterase-4 (PDE4) enzymes are common in immune cells and play a role in controlling inflammation. PDE4 inhibitors prevent these enzymes from breaking down a molecule called cyclic adenosine monophosphate (cAMP), which otherwise would lead to increased inflammation. By blocking this process, PDE4 inhibitors are used to treat various conditions, including skin and lung diseases.

There are two PDE4 inhibitor treatments currently on the market: Crisaborole (sold under brand Eucrisa, Pfizer) and Difamilast (sold under brand Moizerto, Otsuka). Crisaborole was approved by the FDA for the treatment of AD in 2016. Difamilast has been approved in Japan since 2021 and is currently waiting for FDA approval. Difamilast is reported to cause less stinging and itching in the application cite, compared to Crisaborole.⁵

Roflumilast (sold under brand Daxas, AstraZeneca), another PDE4 inhibitor, is an FDA-approved treatment for Psoriasis, but which shows potential for AD. ARQ-151 (Arcutis Biotherapeutics) is a new formulation for AD that contains 0.05% Roflumilast as its active ingredient, specifically designed to provide treatment without disrupting the skin barrier. A 2023 study showed that Roflumilast is safe and effective for treating atopic dermatitis in children. In this phase III trial⁶, 652 children aged 2 to 5 were either treated with ARQ-151 cream or a placebo cream for comparison. By week 4, 25.4% of the children treated with ARQ-151 achieved the primary goal of clear or almost clear skin, compared to 10.7% in the placebo group, with improvements seen as early as week 1. Additionally, 35.3% of the children experienced a significant reduction in itch, and 39.4% showed a reduction in the affected skin area and severity.

The expanding variety of PDE4 inhibitors is enhancing the treatment landscape for AD, offering safer and more effective options, especially for younger patients. With new therapies showing promising results even in children as young as 2 years old, there is hope for improved care and better quality of life across all age groups.

Regulating Transcription Factors: Aryl Hydrocarbon Receptor Agonists

The aryl hydrocarbon receptor (AhR) is a transcription factor that plays a key role in controlling how genes are expressed, influencing processes like metabolism and inflammation. When AhR is activated, it can reduce the release of cytokines, which are proteins that promote inflammation. AhR agonists work by binding to these receptors in skin and immune cells, helping to reduce inflammation. This mechanism is particularly relevant in treating AD, where controlling inflammation is crucial for managing the condition.

Tapinarof (sold under brand Vtama, Dermavant Sciences), is currently the only topical AhR agonist medication being tested for AD. In 2022 it was approved for the treatment of Psoriasis, making it the first new non-steroidal topical product for Psoriasis available in US in two decades. In 2023, a clinical phase III trial was conducted testing Tapinarof for the treatment of AD. The results indicate it to be effective and safe for adults and children.⁷ In the double-blind, randomised, vehicle-controlled phase III study, both adults and children were randomly assigned either a cream containing 1% Tapinarof or a placebo cream. The study aimed to assess the efficacy and safety of Tapinarof cream in treating atopic dermatitis. Participants applied the cream once daily for 8 weeks, with the option to join a 48-week open-label extension study. A total of 406 patients participated, with 46.6% achieving the primary endpoint—a score of clear (0) or almost clear (1)—and 59.1% reaching the secondary endpoint, which measured overall disease severity.

Improving on Ingredients for Delivery

A pivotal advancement for how topical AD treatment could become safer and more effective in the long term is through the medication delivery mechanisms. So far, improvements in delivery mechanisms have only had pre-clinical testing. Improvements in delivery mechanisms through the use of nanoparticles has the potential to make treatment more effective, as well as more targeted which can help lessen side effects – even for natural remedies.

For instance, a 2023 study co-financed by the European Union and the European Regional Development Fund, tested different delivery mechanisms to counter skin inflammation in rats using curcumin. The study found the use of a self-nanoemulsifying drug delivery to administer curcumin effective and also showed it to be able to treat skin inflammation.⁸ Another study (funded by various grants in China) looked at using Salidroside, the main active ingredient in the plant Rhodiola rosea. It was placed in a quaternised β-chitin dextran (QCOD) hydrogel as a carrier to increase the effectiveness of delivery and then used on mice. The study indicated that the gel worked by affecting different signalling pathways.⁹

Studies also looked at improving the delivery of treatments known to work for AD. A 2023 study looked at incorporating the JAK inhibitor Baricitinib (sold under brand Olumiant, Elli Lily & Co.) into different liposomal formulation to see which proved the most effective. Baricitinib is FDA approved for the treatment of rheumatoid arthritis. In liposomal formulations the drug is contained in tiny drug-like particles. Two of the formulations showed similarly promising results, with little irritation, not structural altercations and high Baricitinib retention rates.¹⁰

In a similar vein, studies also looked at improving on JAK inhibitors. In vitro and in vivo testing has been conducted for JAK degraders based on protein degradation targeting chimeras (PROTACs), which would potentially be able to deliver treatment more effectively with less risk. One of them showed greater improvements in AD severity scores compared to Ruxolitinib when tested on mice.¹¹

All of these treatments are still in the early stages of development, and it will take time before they reach the market, provided they prove effective.

Summary of the clinical trials mentioned in this article

What does all this mean for AD?

These advancements present significant commercial opportunities for the pharmaceutical industry. As the treatment landscape shifts from traditional corticosteroids and calcineurin inhibitors to more targeted and safer options, companies that invest in developing and marketing these new therapies stand to gain a substantial competitive edge. The introduction of JAK inhibitors, PDE4 inhibitors, and AhR agonists not only offers differentiation in a crowded market but also allows companies to meet the increasing demand for treatments with improved safety profiles, particularly for children.

The potential for these newer therapies to be less associated with severe side effects could drive higher adoption rates among both clinicians and patients, who may have previously been hesitant to use treatments with known risks. Additionally, the ability to offer more personalised treatment options—where patients can switch between different mechanisms of action if one treatment proves inadequate—can increase patient loyalty.

Furthermore, as these new treatments are increasingly incorporated into standard care guidelines, pharmaceutical companies could see an increase in global market penetration. The ability to market treatments that are safer and more effective could also lead to greater acceptance and approval in regions where regulatory bodies and healthcare systems are particularly cautious about the side effects of existing AD treatments. This global expansion potential is particularly relevant given the widespread prevalence of AD.

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