BenevolentAl Therapeutics Pipeline and Triage

BEN-2293: Excellent skin penetration • Experimental evidence supports high exposure in human skin at >IC90 free, and low exposure in blood with proposed clinical 1% ointment strength. 1% BEN-2293 ointment BID exceeds the exposure needed for PanTrk inhibition in both epidermis/upper dermis and lower dermis even at IC 901 Human in vitro >>IC90 V Healthy skin Non-lesional skin Acute lesional stage Chronic lesional stage Lichenification corneum Skin microbiota Staphylococcus aureus. Barrier dysfunction, innate immune system activation and T 2-driven inflammation and/or T 22-driven inflammation Keratinocyte Variable T1 and T17 activation Stratum Stratum granulosum IL-1ẞ IL-33 TARC IL-25 MDC TSLP Stratum spinosum 000000 Stratum basale Allergen FCER1 IL-33 TSLP Minipig in vitro >> IC90 V Epidermis and upper dermis Minipig in vivo >IC90 V Minipig in vivo Lower Dermis Dermis V Blood Blood vessel Free plasma levels <<400 below IC50 IL-5 IL-13 OX40L IL-4 IL-13 IL-4 IL-13 IgE IL-31 -Cutaneous sensory neuron Eosinophil CLA CCR10 H4R CCR4 CRTH2 ILC2 T2 T22 T1 T 17 Trm B cell T cell Langerhans cell cell cell cell cell cell cell Dermal dendritic cell IDEC CTA-enabling 28d Tox Package: Rat (IV) and Mini-pig (topical) = Safety margins > 20 fold for AUC and > 269 fold for Cmax to dose limited NOAELS 1 (internal Company drug programme data) Benevolent 67 Al

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