Advancing Therapeutic Strategies in Atopic Dermatitis: Emerging Targets and Personalized Approaches
Abstract
1. Introduction
2. Topical Treatments for AD
3. Systemic Treatments for AD
3.1. Biologics and Small Molecule Inhibitors for AD
3.2. Therapies Under Investigation
3.2.1. TSLP and the IL-1 Family
Target | Medication | Study Design | Primary Outcome | Clinical Trial | Status of Investigation |
---|---|---|---|---|---|
TSLP | Tezepelumab | 113 adults with moderate to severe AD | EASI50 at Week 12 Tezepelumab+TCS: 64.7% Placebo+TCS: 48.2% Odds Ratio: 1.97 (95% CI: 0.90 to 4.33) | NCT02525094 (Phase II) [22] | Complete, but failed to meet efficacy |
IL-1α | Bermekimab | 87 adults with moderate to severe AD | EASI75 at Week 16 Bermekimab 400 mg qw: 34.5% (p = 0.04) Bermekimab 400 mg q2w: 24.1% (p = 0.35) Placebo: 13.8% | NCT04021862 (Phase II) [30] | Complete, but failed to meet efficacy |
130 adults with moderate to severe AD | EASI75 at Week 16 Bermekimab 350 mg qw: 16.7% (p = 0.489) Bermekimab 700 mg q2w: 16.7% (p = 0.448) Placebo: 9.5% | NCT04021862 (Phase II) [30] | Terminated due to meeting futility criterion | ||
IL-18 | CMK389 | 71 adults with moderate to severe AD | IGA clear or almost clear and at least a 2-grade improvement from baseline at Week 16 CMK389 10 mg/kg monthly: 14.7% CMK389 300 mg monthly: 11.8% Placebo: 0% | NCT04836858 (Phase II) [34] | Complete |
IL-33 | Astegolimab | 65 adults with moderate to severe AD | % change in the EASI score at Week 16 Astegolimab loading 245 mg/490 mg q4w: −51.47 (8.639) Placebo: −58.24 (9.092) Mean (Standard Error) | NCT03747575 (Phase II) [28] | Complete, but failed to meet efficacy |
Etokimab | 302 adults with moderate to severe AD | % change in the EASI score at Week 16 Etokimab 20 mg q4w: −41.63 (6.707) Etokimab loading 300 mg/150 mg q8w: −55.70 (6.21) Etokimab loading 300 mg/150 mg q4w: −47.40 (6.09) Etokimab loading 600 mg/300 mg q4w: −44.56 (7.81) Placebo: −49.38 (7.12) Mean (Standard Error) | NCT03533751 (Phase II) [35] | Complete, but failed to meet efficacy | |
Itepekimab | 206 adults with moderate to severe AD | % change in the EASI score at Week 16 Itepekimab 300 mg q2w: −66.6 (22.46) Placebo: −52.4 (31.86) Mean (Standard Error) | NCT03736967 (Phase II) [31] | Terminated due to meeting futility criterion | |
IL36R | Spesolimab | 51 adults with moderate to severe AD | % change in the EASI score at Week 16 Spesolimab 600 mg q4w: −37.9 (9.8) Placebo: −12.3 (14.3) (p = 0.149) Mean (Standard Error) | NCT03822832 (Phase II) [32] | Complete, but failed to meet efficacy |
14 adults with moderate to severe AD | Number of patients with treatment emergent adverse events at week 48: 9/14 (64.3%) | NCT04086121 (Phase II) Open Label Extension Study of NCT03822832 [36] | Terminated |
3.2.2. OX40 and OX40L
Target | Medication | Study Design | Primary Outcome | Clinical Trial | Status of Investigation |
---|---|---|---|---|---|
OX40L | Amlitelimab | 89 adults with moderate to severe AD | % change in the EASI score at Week 16 Amlitelimab loading 200 mg/100 mg q4w: −80.12% (95% CI: −95.55 to −64.68) (p = 0.009) Amlitelimab loading 500 mg/250 mg q4w: −69.97% (95% CI: −85.04 to −54.60) (p = 0.07) Placebo: −49.37% (95% CI: −66.02 to −32.72) | NCT03754309 (Phase II) [48] | Complete |
390 adults with moderate to severe AD | % change in the EASI score at Week 16 Amlitelimab loading 500 mg/250 mg q4w: −61.5% (95% CI: −43.9 to −20.3) (p < 0.0001) Amlitelimab 250 mg q4w: −56.8% (95% CI: −39.1 to −15.6) (p < 0.0001) Amlitelimab 125 mg q4w: −51.6% (95% CI: −34.0 to −10.4) (p = 0.0002) Amlitelimab 62.5 mg q4w: −59.6% (95% CI: −41.9 to −18.5) (p < 0.0001) Placebo: −29.4% | NCT05131477 (Phase II) [47] | Complete | ||
OX40 | Rocatinlimab (AMG 451/KHK4083) | 274 adults with moderate to severe AD | % change in the EASI score at Week 16 Rocatinlimab 150 mg q4w: −48.33 (95% CI: −62.62 to −34.04) Rocatinlimab 600 mg q4w: −49.72 (95% CI: −62.47 to −35.17) Rocatinlimab 300 mg q2w: −61.07 (95% CI: −75.19 to −46.96) Rocatinlimab 600 mg q2w: −57.35 (95% CI: −71.27 to −43.43) Placebo: −15.01 (95% CI: −28.60 to −1.43) Statistically significant improvements in all groups | NCT03703102 (Phase II) [44] | Complete |
OX40 | Telazorlimab (ISB 830/ GBR 830) | 64 adults with moderate to severe AD | Change from baseline in lesional epidermal thickness at week10 Telazorlimab 10 mg/kg q4w: −26.51 (88.68) Placebo: −6.01 (39.40) | NCT02683928 (Phase II) [45] | Complete |
462 adults with moderate to severe AD | % change in the EASI score at Week 16; Mean (Standard Error) Telazorlimab loading 600 mg/300 mg q2w: −54.4 (5.1) (p = 0.008) Telazorlimab loading 600 mg/300 mg q4w: −48.6 (5.4) (p = 0.06) Telazorlimab loading 150 mg/75 mg q4w: −31.0 (5.7) (p = 0.69) Placebo 2 injections q2w: −34.2 (5.5) Telazorlimab loading 1200 mg/600 mg q2w: −59.0 (4.6) (p = 0.008) Placebo 4 injections q2w: −41.8 (4.7) | NCT03568162 (Phase II) [46] | Complete | ||
IL-12/ IL-23 | Ustekinumab | 79 Japanese adults with severe AD | % change in the EASI score at Week 12; Mean (Standard Error) Ustekinumab 45 mg at Week 0 and 4: −38.62 (32.684) Ustekinumab 90 mg at Week 0 and 4: −39.39 (38.710) Placebo: −37.54 (37.592) Both treatment arms allowed concurrent use of TCS, topical calcineurin inhibitors, or anti-leukotriene therapies | NCT01945086 (Phase II) [49] | Complete, but failed to meet efficacy |
32 adults with moderate to severe AD | SCORAD50 at Week 16 Ustekinumab+TCS: 31.3%; Placebo+TCS: 18.8% Odds Ratio: 1.93 (95%CI: 0.30 to 15.33) | NCT01806662 (Phase II) [50] | Complete, but failed to meet efficacy | ||
IL-23 | Risankizumab | 172 adults and adolescents with moderate to severe AD | EASI75 at Week 16 Risankizumab 150 mg at Week 0 and 4: 24.6% (95%CI: 14.5 to 34.8) (p = 0.08) Risankizumab 300 mg at Week 0 and 4: 21.7% (95%CI: 12.0 to 31.5) (p = 0.18) Placebo: 11.8% (95%CI: 0.9–22.6) | NCT03706040 (Phase II) [51] | Complete, but failed to meet efficacy |
IL-17 | Secukinumab | 41 adults with moderate to severe AD | Fold change in epidermal thickness of lesional skin at Week 16 Secukinumab only for extrinsic AD: 1.18 (1.15) Secukinumab only for intrinsic AD: −1 (1.15) Placebo then secukinumab from week 16 for extrinsic AD: 1.15 (1.22) Placebo then secukinumab from week 16 for intrinsic AD: 1.5 (1.3) | NCT02594098 (Phase II) [52] | Complete, but failed to meet efficacy |
IL-22 | Fezakinumab (ILV-094) | 60 adults with moderate to severe AD | % change in the SCORAD at Week 12 Fezakinumab loading 600 mg/300 mg q2w: −13.8 (2.7) Placebo: −8 (3.1) (p = 0·134) % change in the SCORAD at Week 20 Fezakinumab loading 600 mg/300 mg q2w: −18.8 (2.9) Placebo: −11.7 (3.9) (p = 0·049) | NCT01941537 (Phase II) [53] | Complete |
3.2.3. IL-17 and Th17-Related Cytokines
3.2.4. IL-22
4. Special Consideration for AD
4.1. Modulation of the Skin Microbiome
4.2. The Itch–Scratch Cycle
4.2.1. IL-31
4.2.2. Histamine 4 Receptor (H4R)
4.2.3. Substance P (SP) and Neurokinin 1 Receptor (NK1R)
5. Challenging and Future Perspectives
6. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
AD | atopic dermatitis |
Th2 | T helper 2 |
IL | interleukin |
JAK/STAT | Janus kinase/signal transducer and activator of transcription |
TSLP | thymic stromal lymphopoietin |
EASI | eczema area and severity index |
POEM | patient-oriented eczema measure |
DLQI | dermatology life quality index |
PP-NRS | peak pruritus numerical rating scale |
TCS | topical corticosteroids |
RCT | randomized controlled trial |
H4R | Histamine 4 Receptor |
IGA | Investigator’s Global Assessment |
NK1R | neurokinin 1 receptor |
SP | Substance P |
SCORAD | SCORing Atopic Dermatitis |
TSLP | thymic stromal lymphopoietin |
WI-NRS | worst itch numeric rating scale |
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Target | Medication | Study Design | Primary Outcome | Clinical Trial | Status of Investigation |
---|---|---|---|---|---|
Antibacterial activity | Topical staphylococcus hominis A9 | 54 patients with AD with positive S. aureus culture colonized lesion | Per-participant daily event rate of treatment-emergent adverse event targeted microbiome transplant: 0.19 (95% CI: 0.12 to 0.29) Placebo: 0.34 (95% CI: 0.20 to 0.58) p = 0.075 | NCT03151148 (Phase I) [72] | Complete |
Topical biotherapeutic B244 | 547 patients with AD with mild to moderate pruritus | Mean change in WI-NRS at Week 4 B244 O.D. 5.0: −2.8 (0.184) (p = 0.0148) B244 O.D. 20.0: −2.8 (0.184)(p = 0.0143) Placebo: −2.1 (0.180) | NCT04490109 (Phase II) [73] | Complete | |
Topical omiganan | 37 adults with AD | Change in local objective SCORAD index at Week 4 Omiganan 2.5%: −18.5% (95% CI: −32.9% to −1.0%) (p = 0.04) Omiganan 1%: −13.4% (95% CI: −28.4% to 4.6%) (p = 0.13) | NCT02456480 (Phase II) [75] | Complete | |
80 adults with mild to moderate AD | Abundance of Staphylococcus at Week 4 Omiganan 1%: −15.1 (95% CI, −28.6 to −1.7) (p = 0.03) Omiganan 2.5%: −17.2 (95% CI, −30.4 to −4.1) (p = 0.01) Change in local objective SCORAD index at Week 4 Omiganan 1%: 2.0 (95% CI: 0.52 to 4.51) (p = 0.12) Omiganan 2.5%: 2.52 (95% CI: 0.0 to 5.04) (p = 0.05) | NCT03091426 (Phase II) [74] | Complete | ||
Topical Roseomonas mucosa (FB-401) | 154 patients (age ≥ 2 years) with mild to moderate AD | EASI 50 at Week 16 FB−401 3 times per week: 57.9% (p = 0.7567) Placebo: 60.3% | NCT04504279 (Phase II) [76] | Complete, but failed to meet efficacy |
Target | Medication | Study Design | Primary Outcome | Clinical Trial | Status of Investigation |
---|---|---|---|---|---|
IL-31RA | Nemolizumab | 143 Japanese (age ≥ 13 years) with AD and moderate-to-severe pruritus | % change in the VAS score for pruritus at week 16 Nemolizumab 60 mg q4w: −42.8% Placebo: −21.4% least-squares mean difference between two groups: −21.5% (95% CI: −30.2 to −12.7; p < 0.001) | JapicCTI-173740 [97] | Complete |
89 Japanese patients (age ≥ 6 and < 13 years) with AD and moderate-to-severe pruritus | Change in 5-level itch score from baseline at week 16 Nemolizumab 30 mg q4w: −1.3 Placebo: −0.5 Least-squares mean difference between two groups: −0.8 (95% CI: −1.1 to −0.5; p < 0.0001) | Japan Registry for Clinical Trials 2080225289 [95] | Complete | ||
941 patients (age ≥ 12 years) with moderate to severe AD | IGA clear or almost clear and at least a 2-grade improvement from baseline at Week 16 Nemolizumab loading 60 mg/30 mg q4w: 35.6% (p = 0.0003) Placebo: 24.6% EASI75 at Week 16 Nemolizumab loading 60 mg/30 mg q4w: 43.5% (p < 0.0001) Placebo: 29.0% | NCT03985943 (Phase III) [96] | Complete | ||
787 patients (age ≥ 12 years) with moderate to severe AD | IGA clear or almost clear and at least a 2-grade improvement from baseline at Week 16 Nemolizumab loading 60 mg/30 mg q4w: 37.7% (p = 0.0006) Placebo: 26.0% EASI75 at Week 16 Nemolizumab loading 60 mg/30 mg q4w: 42.1% (p = 0.0006) Placebo: 30.2% | NCT03989349 (Phase III) [96] | Complete | ||
H4R | ZPL-3893787/ Adriforant | 98 adults with moderate to severe AD | Reduction of WI-NRS at week 8 Adriforant 30 mg QD: −3.03 (2.186) (p = 0.249) Placebo: −2.66 (2.057) | NCT02424253 (Phase II) [98] | Complete but failed to meet efficacy |
LEO 152020 | 216 adults with AD | Change in the EASI score at Week 16 LEO 152020(Higher Dose): −9.99 (95% CI: −12.85 to −7.13) LEO 152020(Middle Dose): −8.83 (95% CI: −12.63 to −5.04) LEO 152020(Lower Dose): −8.87 (95% CI: −12.47 to −5.28) Placebo: −9.11(95% CI: −11.88 to −6.35) | NCT05117060 (Phase II) [99] | Complete but failed to meet efficacy | |
JNJ 39758979 | 88 Japanese adults with moderate AD | Changes in EASI scores at Week 6 JNJ−39758979 100 mg: median, −3.70 (p = 0.1672) JNJ−39758979 300 mg: median, −3.00 (p = 0.1992) placebo: median, −1.30 | NCT01497119 (Phase II) [100] | Terminate due to 2 cases of agranulocytosis | |
NK1R | Tradipitant | 375 adults with AD suffering from chronic pruritus | Reduction of WI-NRS at week 8 Mean (Standard Deviation) Oral tradipitant BID: −3.6 (2.8) Placebo: −3.5 (2.75 | NCT03568331 (Phase III) [101] | Complete but failed to meet efficacy |
87 adults with AD suffering from chronic pruritus | WI-NRS responder rate at week 2 (achieve at least 4 points reduction from baseline) Oral tradipitant BID: 4.8% Placebo: 9.3% | NCT04140695 (Phase III) [102] | Terminate | ||
Serlopitant | 484 patients (age ≥ 13 years) AD with pruritus | Reduction of WI-NRS at week 6 Oral serlopitant loading 15 mg/5 mg QD: −2.25 (2.198) Oral serlopitant loading 3 mg/1 mg QD: −2.32 (2.418) Placebo: −2.01 (2.212) | NCT02975206 (Phase II) [103] | Complete but failed to meet efficacy |
Target Symptom | Therapeutic Strategy | Example |
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Skin Inflammation |
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Itch |
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Secondary Infection/Colonization |
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Lo, Y.; Cheng, T.-T.; Huang, C.-J.; Cheng, Y.-C.; Chyuan, I.-T. Advancing Therapeutic Strategies in Atopic Dermatitis: Emerging Targets and Personalized Approaches. Biomolecules 2025, 15, 838. https://doi.org/10.3390/biom15060838
Lo Y, Cheng T-T, Huang C-J, Cheng Y-C, Chyuan I-T. Advancing Therapeutic Strategies in Atopic Dermatitis: Emerging Targets and Personalized Approaches. Biomolecules. 2025; 15(6):838. https://doi.org/10.3390/biom15060838
Chicago/Turabian StyleLo, Yang, Ting-Ting Cheng, Chi-Jung Huang, Yu-Che Cheng, and I-Tsu Chyuan. 2025. "Advancing Therapeutic Strategies in Atopic Dermatitis: Emerging Targets and Personalized Approaches" Biomolecules 15, no. 6: 838. https://doi.org/10.3390/biom15060838
APA StyleLo, Y., Cheng, T.-T., Huang, C.-J., Cheng, Y.-C., & Chyuan, I.-T. (2025). Advancing Therapeutic Strategies in Atopic Dermatitis: Emerging Targets and Personalized Approaches. Biomolecules, 15(6), 838. https://doi.org/10.3390/biom15060838