The atopic dermatitis (AD) space will completely transform over the next decade due to intense clinical activity, says GlobalData. The leading data and analytics company notes that 64% of the pipeline consists of small molecular agents while the rest comprises biologics. Most of these are interleukin inhibitors hoping to follow in the footsteps of dupixent. However, there are some novel drug classes adding flare to the AD pipeline, including sphingosine 1-phosphate receptor (S1PR) modulators and OX40 inhibitors. The latter classes will help diversify the pipeline and act as a catalyst for more innovation in the AD realm.

Ramla Salad, Pharma Analyst at GlobalData, comments: “The AD space has seen a dramatic rise in interest from the pharmaceutical industry, which is exemplified by the sheer size of its clinical development pipeline. An increasing number of companies are seeing the potential in this indication for its return on investment, and are entering the space singularly or through strategic partnerships. The introduction of unique drug classes to the AD space will provide patients with a plethora of options and will give doctors more choice although this may come with further scrutiny especially for the JAK class.”

Having analysed all pipeline products currently in Phase I, II, and III stages of clinical development for AD within the seven major markets (7MM*), Salad notes some key movements within the pipeline:

A total 35% of the pipeline agents are in Phase I trials, while 55% are in Phase II and 10% are in Phase III. Small molecule agents make up 64% of the pipeline and include multiple late-stage JAK inhibitors and PDE4 inhibitors, among other mechanisms of action. Key late-stage JAK inhibitors include three oral agents, AbbVie’s Rinvoq (upadacitinib), Pfizer’s abrocitinib and Asana Bioscience’s gusacitinib, as well as two topical agents, Incyte’s ruxolitinib and Pfizer’s brepocitinib.

Among the PDE4 inhibitors, some notable late-stage products are Otsuka Pharmaceutical/Medimetriks’ difamilast and Arcutis Biotherapeutics’ roflumilast. These agents are only being developed for topical use in AD.

Salad notes: “While the majority of JAK inhibitors in late-stage development are targeting moderate-to-severe patients, ruxolitinib and brepocitinib are being positioned for patients with mild-to-moderate AD. The potential availability of a new mechanism of action for patients with milder disease could have strong impacts on AD market dynamics.

“Difamilast and roflumilast are set to follow Pfizer’s Eucrisa (crisaborole), a widely used topical PDE4 inhibitor for mild-to-moderate AD. The topical route of administration is clearly a huge focus for investigators involved in AD clinical development.”

Biologics make up 36% of the AD pipeline but there is one particularly notable class—the interleukin (IL) inhibitors. Key late-stage IL inhibitors include AbbVie’s risankizumab (anti-IL-23), Galderma’s nemolizumab (anti-IL-31), Eli Lilly’s lebrikizumab (anti-IL-13) and Janssen’s bermekimab (anti-IL-1). All these IL agents have a novel MOA thus bringing diversity to the AD space.

Salad comments: “These IL-inhibiting agents are following in the footsteps of Sanofi/Regeneron’s Dupixent (dupilumab), a first-in-class IL-4/IL-13 dual inhibitor approved for the treatment of moderate-to-severe AD since 2019. With global reported sales of over $4bn in 2020, Dupixent has seen strong uptake in AD, signalling the market’s readiness for other IL inhibitors.”

Other notable mechanisms of action within the late- and early-stage pipelines are the biologic OX40 inhibitors and small molecule sphingosine 1-phosphate receptor (S1PR) modulators. These novel approaches showcase the ground-breaking research and development going on in this area.

Salad continues: Among the OX40 agents, Kyowa Kirin/Amgen’s KHK-4083 is ready for Phase III assessment, while Kymab’s KY-1005 and Ichnos Sciences’ telazorlimab are still completing Phase II trials. The anti-OX40 class uses a completely novel mechanism of action, and early data suggests it could disrupt the AD treatment paradigm.

“Arena Pharmaceutical’s etrasimod is a progressive new oral therapy within the S1PR class that is ready for Phase III, with a pivotal study program expected to begin in H2 2021. There are no S1PR modulators on the market for AD, so etrasimod would be a first-in-class agent if it is brought to market. While S1PR modulators will need to compete with the rapidly growing JAK inhibitor class, safety could end up being a key differentiator for these agents.”

All biologics in development for AD are administered subcutaneously.

Salad adds: “Although injections may not be preferred by some, they can be an attractive option for patients because they are administered less frequently (every two to four weeks), which could increase compliance. However, topical creams could prove popular in the paediatric group due to the ease of application.”

* The US, Japan, France, Germany, Italy, Spain and the UK