Atopic Dermatitis: Novel Therapeutic Targets and Pathways1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/KCX40

Biologic Agents and Specific Targets in the Pathogenesis of AD

Pruritus Itching Epidermal Barrier Dysfunction Lichenification

Microbiome Antimicrobial peptides Etokimab Keratinization MOR 106 Allergens (Filaggrin, Loricrin) Th1 products Epidermal hyperplasia IL-33 IL-17C

Fezakinumab

Tezepelumab TSLP Th2 IL-22

Nemolizumab KPL-716 IL-13Rα2 TSLPR MK-8226 IL-31RA OSMRβ Allergens

IL-13Rα1 IL-13 IL-4 IL-4Rα IL-4Rα IgE B IL-13 IL-13 IL-17A

γc

BMS-981164 IL-31 OX40L IL-12/23 (p40) GBR 830 OX40

Eosinophil KHK 4083 recruitment IL-4 Th22 IL-5 Th1 Naïve T lymphocyte Th2 Th17 IL-13

Mepolizumab

Acute Phase Chronic Phase Atopic Dermatitis: Novel Therapeutic Targets and Pathways1 Full abbreviations, accreditation, and disclosure information available at PeerView.com/KCX40

Small Molecules and Specific Targets in the Pathogenesis of AD

Pruritus Itching Epidermal Barrier Dysfunction Lichenification

Substance P Asimadoline PGE1 Serlopitant DS107 NK-1R kOR Tradipitant DGLA PGD1 Anti-inflammatory effects: ↓ activation H4R Histamine ↓TSLP K opioids ↓Mastocyte activation JNJ-39758979 PGD2

Mastocyte ZPL389 AC

Mastocyte ATP ASN002 (Pan-JAK) PDE4

Upadacitinib cAMP

Abrocitinib IL13Rα1 IL-4Rα IL-4Rα

γc PKA JAK 1 JAK 3 JAK 1/2 Tyk2

STAT STAT STAT STAT

CREB NFκB NFAT Sensory neurons

STAT Transcription cytokines STAT

1. Munera-Campos M, Carrascosa JM. Actas Dermosifiliogr. 2020;111:205-221. Biologic Agents and Small Molecules in Advanced Stage of Development for the Treatment of Atopic Dermatitis Full abbreviations, accreditation, and disclosure information available at PeerView.com/KCX40

Subcutaneously Administered Biologic Agents

Therapeutic Currently Recruiting Phase 3 Studies Agent Clinical Trials With Efficacy and Safety Results Target (ClinicalTrials.gov Identifier)

• Study to Assess the Safety and Efficacy of Lebrikizumab in Adolescent Participants With Moderate-to-Severe AD (ADore; NCT04250350) 1 • Phase 2b • Long-Term Safety and Efficacy Study of Lebrikizumab in Participants – Double-blind, placebo-controlled, dose-ranging IL-13 With Moderate-to-Severe AD (ADjoin; NCT04392154) Lebrikizumab randomized trial of lebrikizumab in patients ≥18 years with moderate to severe AD • Safety and Efficacy of Lebrikizumab in Combination With Topical Corticosteroid in Moderate-to-Severe AD (ADhere; NCT04250337) • A Study of Lebrikizumab in Combination With TCS in Japanese Participants With Moderate-to-Severe AD (ADhere-J; NCT04760314)

• ECZTRA 1 and ECZTRA 22 – Tralokinumab monotherapy in adults ≥18 years with moderate to severe AD who had an inadequate IL-13 response to topical treatments N/A Tralokinumab (IL-13Rα1 3 and IL-13Rα2) • ECZTRA 3 – Tralokinumab + TCS in patients ≥18 years with moderate to severe AD who were candidates for systemic therapy3

• Phase 2b4 – Nemolizumab + TCS in adults ≥18 years with moderate • Efficacy and Safety of Nemolizumab in Subjects With to severe AD, severe pruritus, and inadequate control Moderate-to-Severe Atopic Dermatitis (NCT03985943) with topical treatment • Efficacy and Safety of Nemolizumab in Subjects With Nemolizumab IL-31RA • Phase 35 Moderate-to-Severe Atopic Dermatitis (NCT03989349) – Japanese patients ≥13 years with AD and moderate • Long-Term Safety and Efficacy of Nemolizumab With to severe pruritus and an inadequate response Moderate-to-Severe Atopic Dermatitis (NCT03989206) to topical agents Biologic Agents and Small Molecules in Advanced Stage of Development for the Treatment of Atopic Dermatitis Full abbreviations, accreditation, and disclosure information available at PeerView.com/KCX40

Orally Administered Small-Molecule JAK Inhibitors

JAK Currently Recruiting Phase 3 Studies Agent Clinical Trials With Efficacy and Safety Results Selectivity (ClinicalTrials.gov Identifier)

• JADE-MONO-16 – Abrocitinib monotherapy in patients ≥12 years with moderate to severe AD and recent history of inadequate response or inability to tolerate topical AD treatments or require systemic treatments for AD control • JADE-MONO-27 – Abrocitinib monotherapy in patients ≥12 years with moderate to severe AD and recent history of inadequate response or inability to tolerate topical AD treatments or require systemic treatments for AD control • JADE COMPARE8 N/A Abrocitinib JAK1 – Abrocitinib versus placebo or dupilumab in patients ≥18 years with moderate to severe AD that was unresponsive to topical agents or warranted systemic therapy • JADE TEEN9 – Abrocitinib versus placebo in adolescents 12-17 years with moderate to severe AD • JADE REGIMEN10 – Abrocitinib in patients ≥12 years with moderate to severe AD with the option of rescue treatment in flaring subjects • JADE EXTEND11 – Abrocitinib in patients ≥18 years with moderate to severe AD who did not respond to dupilumab in JADE COMPARE

• BREEZE‐AD1 and BREEZE‐AD212 – Baricitinib monotherapy in patients ≥18 years with moderate to severe AD who had an inadequate response to topical therapies • A Study of Baricitinib in Participants • BREEZE-AD313 With Moderate to Severe – Long-term study of baricitinib in patients ≥18 years with moderate to severe AD Atopic Dermatitis (BREEZE-AD6; • BREEZE-AD 14 NCT03559270) Baricitinib JAK1/2 – Baricitinib + TCS in patients ≥18 years with moderate to severe AD who have experienced failure to cyclosporine or are intolerant to or have contraindication to cyclosporine14 • A Study of Baricitinib (LY3009104) • BREEZE-AD5 15 in Children and Adolescents With – Baricitinib monotherapy in patients ≥18 years with moderate to severe AD who responded inadequately or were Atopic Dermatitis (BREEZE-AD-PEDS; intolerant to topical therapy NCT03952559) • BREEZE-AD7 16 – Baricitinib + TCS in patients ≥18 years with moderate to severe AD who previously had an inadequate response to TCS therapy • MEASURE Up 1 and MEASURE Up 217 – Upadacitinib monotherapy in patients ≥12 years with moderate to severe AD who are candidates for systemic treatment • AD UP18 Upadacitinib JAK1 N/A – Upadacitinib + TCS in patients ≥12 years with moderate to severe AD who are candidates for systemic treatment • HEADS Up19 – Upadacitinib versus dupilumab in patients ≥18 years with moderate to severe AD who are candidates for systemic therapy

1. Guttman-Yassky E et al. JAMA Dermatol. 2020;156:411-420. 2. Wollenberg A et al. Br J Dermatol. 2021;184:437-449. 3. Silverberg JI et al. Br J Dermatol. 2021;184:450-463. 4. Silverberg JI et al. J Clin Immunol. 2020;145:173-182. 5. Kabashima K et al. N Engl J Med. 2020;383:141-150. 6. Simpson EL et al. Lancet. 2020;396:255-266. 7. Silverberg JI et al. JAMA Dermatol. 2020;156:863-873. 8. Bieber T et al. N Engl J Med. 2021;384:1101-1112. 9. Eichenfield L et al. 2021 American Academy of Allergy, & Immunology Annual Meeting. Abstract 467. 10. Blauvelt A et al. 2021 American Academy of Dermatology Virtual Meeting Experience (2021 AAD VMX). Session S033: Late-breaking abstracts. 11. Shi V et al. 2021 AAD VMX. Poster 27590. 12. Simpson EL et al. Br J Dermatol. 2020;183:242-255. 13. Silverberg J et al. 2020 European Academy of Dermatology and Venereology Virtual Congress (EADV 2020). Abstract D3T03.4D. 14. https://www.prnewswire.com/news-releases/lilly-and-incyte-announce-top-line-results-from-phase-3-study-breeze-ad4-of-oral-selective-jak-inhibitor-baricitinib-in-combination-with-topical-corticosteroids-in​ -patients-with-moderate-to-severe-atopic-dermatitis-not-controlle-300993285.html. 15. Simpson EL et al. J Am Acad Dermatol. 2021;S0190-9622(21)00353-4. 16. Reich K et al. JAMA Dermatol. 2020;156:1333-1343. 17. Guttman-Yassky E et al. Lancet. 2021;S0140-6736(21)00588-2. 18. Reich K et al. Lancet. 2021;S0140-6736(21)00589-4. 19. https://www.prnewswire.com/news-releases/rinvoq-upadacitinib-achieved-superiority-versus-dupixent-dupilumab-for-primary-and-all-ranked-secondary-endpoints-in-phase-3b-head-to-head-study-in-adults-with-atopic​ -dermatitis-301190344.html.