BenevolentAl Therapeutics Pipeline and Triage

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

View entire presentation