Topical Janus kinase (JAK) inhibitors are becoming a major force in the atopic dermatitis (AD) space, with an increasing number of agents filling the early and late-stage pipeline. Figure 1 highlights six topical JAK inhibitor products currently in clinical development for the treatment of AD.

In the realm of topical JAK inhibitors, Incyte leads the pack with its JAK1/2 inhibitor ruxolitinib, already marketed in an oral formulation (branded as Jakafi) for the treatment of myelofibrosis. In the Phase III trial, TRuE-AD2 (NCT03745651), 39.0% of patients treated with ruxolitinib 0.75% twice daily and 51.3% treated with ruxolitinib 1.5% twice daily met the primary endpoint of IGA-TS, compared to only 7.6% of patients treated with placebo. Ruxolitinib is currently under US Food and Drug Administration (FDA) review for the treatment of AD, but the Prescription Drug User Fee Act (PDUFA) date has been extended to the third quarter of this year. The drug is also currently being reviewed by the European Medicines Agency (EMA) with approval anticipated by the fourth quarter of this year.

Incyte recently registered a second Phase III trial (TRuE-AD3) assessing the efficacy and safety of ruxolitinib in children aged 2–12. This move signals confidence by the company regarding the approval of ruxolitinib cream in adults, and suggests the company is looking to greatly expand its market potential by targeting paediatric patients, a similar tactic as that used by Pfizer with its topical PDE4 inhibitor Eucrisa (crisaborole).

Ruxolitinib’s closest competitor thus far is Leo Pharma’s delgocitinib, a topical pan-JAK inhibitor tailored towards patients suffering from chronic hand eczema (CHE). CHE is a type of atopic dermatitis that affects the back of the hands and fingers. Symptoms can last for more than three months, thus having a negative impact on psychological and social aspects of patients’ lives.

Delgocitinib’s Phase IIb (NCT03683719) data showed a dose-dependent response to twice-daily doses of 8mg/g and 20mg/g, demonstrating the highest efficacy in adults with mild-to-severe CHE. By week 16 of treatment, almost 40% of patients receiving either dose were clear or almost clear of symptoms as assessed by IGA-CHE. This is promising as symptoms in CHE typically persist for at least three months.

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Phase III development of delgocitinib began in May and top-line data are expected near the end of next year. Although it will likely be second-to-market behind ruxolitinib, delgocitinib’s FDA fast track designation (FTD), awarded in the third quarter of last year in response to the unmet need surrounding CHE, will help to expedite the regulatory process. Delgocitinib is already approved in Japan under the name Corectim for adult and, more recently, paediatric AD patients.

The other topical JAK inhibitor agents in the pipeline for AD are in earlier stages of development. Aclaris Therapeutics’ JAK 1/3 inhibitor, ATI-1777, recently announced positive preliminary Phase IIa data in the treatment of CHE. These data will support the initiation of the company’s planned Phase IIb. Both delgocitinib and ATI-1777 are targeting a unique patient population with a great unmet need and, if efficacious, will likely take precedence over existing therapies due to the localisation of treatment.

Arcutis Biotherapeutics’ asset, ARQ-252, is differentiated from other topical JAK inhibitors as it is JAK1-specific, which could help dampen ongoing safety concerns seen more commonly with multi-JAK inhibitors. If proven to be effective, however, Pfizer’s PF-06700841, a Tyk2/JAK1 inhibitor, would also have a major advantage, as the company is already strongly rooted in the AD space with the only topical on the market, Eucrisa. Novartis’ pan-JAK inhibitor, CEE321, is currently the agent in the earliest stages of development for AD, with a proof-of-concept Phase I study ongoing in the US and Japan. The company specifically mentioned AD as a lead indication in its Q1 2021 update, meaning it likely has a strategic direction for this asset.

JAK inhibitors are making strong headway in the AD market; ruxolitinib is leading the topicals, with delgocitinib not far behind with an FTD. ATI-1777 is meeting key milestones with development moving along, and could prove to be an innovative addition to the market. ARQ-252, PF-06700841 and CEE321 are still building an evidence base, but Pfizer and Novartis are big players in the immunology field with solid in-house expertise.

The expansion of the topical JAK inhibitor drug class is advantageous for patients, as it will diversify treatment options while simultaneously increasing compliance. There is also the possibility that a topical route of administration may help these products circumvent the regulatory hurdles that oral JAK inhibitors are currently facing.