Benevolent Platform Precision Medicine

Atopic Dermatitis - BEN-2293, pan-Trk inhibition rationale Healthy skin Non-lesional skin Acute lesional stage Chronic lesional stage Lichenification corneum Skin microbiota Staphylococcus aureus. Barrier dysfunction, innate immune system activation and T2-driven inflammation and/or T 22-driven inflammation Keratinocyte Variable T1 and T17 activation Allergen TrkC • NT3/TrkC potentiates stimulated Th2 T-cell inflammatory responses and synergistically enhances T-cell receptor induced IL-4 production by Th2 cells • Mast cells within AD skin lesions express high levels of NT3 compared to normal controls Stratum Stratum basale TrkB • AD Skin-resident eosinophils express elevated levels of TrkB (together with TrkA and C) and functionally respond to BDNF • BDNF/TrkB inhibit eosinophil • apoptosis and increase chemotactic index Scatum gralosum Stratum spinosum IL-1ẞ IL-33 TARC IL-25 MDC TSLP FCER1 IL-33 TSLP Dermis Blood vessel IL-4 IL-13 OX40L Eosinophil CLA CCR10 H4R CCR4 CRTH2 IL-4 IL-13 IgE IL-31 -Cutaneous sensory neuron ILC2 B cell T cell T2 T22 T1 T17 Trm cell cell cell cell cell cell Langerhans cell O Dermal dendritic cell IDEC TrkA • TrkA levels in skin dramatically increase in response to inflammatory stimuli NGF produced by AD keratinocytes, is a major mediator of cutaneous hyperinnervation • Increased NGF in the skin sensitizes primary afferents contributing to peripheral itch sensitization and chronic pruritus Involved in the inflammatory activation of mast cells and basophils ΑΙ Benevolent 66

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