What are the emerging therapies targeting atopic dermatitis?

Emerging Targeted Therapies for Atopic Dermatitis

The most promising emerging therapies for atopic dermatitis include biologics targeting specific interleukins (IL-13 inhibitors like lebrikizumab and tralokinumab), JAK inhibitors (abrocitinib, baricitinib, and upadacitinib), and small molecule therapies targeting intracellular pathways. These treatments represent significant advances in addressing the complex immunopathogenesis of atopic dermatitis with greater precision than traditional immunosuppressants.

Biologics Targeting Specific Cytokines

IL-13 Inhibitors

• Lebrikizumab: Recently approved biologic that specifically targets IL-13, showing significant efficacy in moderate-to-severe atopic dermatitis with 43% of patients achieving clear or almost clear skin (IGA 0/1) and 59% achieving EASI-75 at week 16 1
• Tralokinumab: Targets IL-13 specifically, with demonstrated efficacy in moderate-to-severe atopic dermatitis 2

These biologics represent an advancement from dupilumab (which targets both IL-4 and IL-13) by offering more selective targeting of the Th2 inflammatory pathway.

JAK Inhibitors

The Taiwan Academy of Pediatric Allergy, Asthma and Immunology and American Academy of Dermatology strongly recommend oral JAK inhibitors for moderate-to-severe atopic dermatitis 3:

• Abrocitinib: Oral JAK1 inhibitor
• Baricitinib: Oral JAK1/JAK2 inhibitor
• Upadacitinib: Oral selective JAK1 inhibitor

JAK inhibitors offer several advantages over biologics:

• Oral administration route
• Faster onset of action
• Potentially higher efficacy based on network meta-analyses 4

However, they require more careful monitoring due to safety concerns extrapolated from older JAK inhibitors used in other conditions 4.

Emerging Topical Therapies

Several novel topical treatments are in development 3, 5:

• Topical PDE-4 inhibitors: Crisaborole has been approved for mild to moderate AD in patients aged 3 months and above 3
• Topical JAK inhibitors: Delgocitinib and ruxolitinib showing promise in clinical trials 5
• Aryl hydrocarbon receptor modulators: Novel mechanism targeting skin barrier function 5
• Nitric oxide-releasing particles: SB204 has shown efficacy in reducing inflammatory lesions in phase 2 studies 3

Small Molecule Therapies

Beyond JAK inhibitors, several other small molecule approaches are being investigated 5:

• STAT6 degraders (KT621, NX3911): Target the downstream signaling of IL-4/IL-13
• Histamine H4 receptor antagonists (adriforant, izuforant): Address the pruritus component
• Sphingosine-1-phosphate receptor modulators (etrasimod, BMS-986166): Regulate lymphocyte trafficking

Clinical Decision Framework

When selecting among emerging therapies:

1. For moderate-to-severe AD unresponsive to topical therapy:

   • First consider biologics (dupilumab, tralokinumab, lebrikizumab) if safety is the primary concern
   • Consider JAK inhibitors (upadacitinib, abrocitinib) if rapid response is needed or injectable therapy is not preferred

2. For mild-to-moderate AD:

   • Consider topical PDE-4 inhibitors like crisaborole as steroid-sparing alternatives
   • Emerging topical JAK inhibitors may provide additional options

Considerations and Caveats

• Safety monitoring: JAK inhibitors require more rigorous monitoring than biologics due to potential risks of serious infections, thromboembolism, and malignancy 3, 4

• Treatment selection: Network meta-analyses suggest higher doses of abrocitinib and upadacitinib may be more effective than biologics, while among biologics, dupilumab appears more effective than tralokinumab and lebrikizumab 4

• Conflict of interest awareness: When evaluating new systemic treatments, be aware that clinical practice guidelines may be influenced by authors with ties to pharmaceutical companies developing these agents 3

• Combination approaches: Many clinical trials allow concomitant use of topical therapies alongside these newer systemic agents, which may enhance real-world effectiveness 3

The rapid expansion of targeted therapies for atopic dermatitis represents a significant advancement from traditional immunosuppressants like cyclosporine, methotrexate, and azathioprine, offering more precise immune modulation with potentially improved safety profiles.