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Evommune — American Headache Society (AHS) Annual Scientific Meeting (June 2026)

14 slides from Evommune's conference presentation, June 2026

  1. Slide 1: Dual Inhibition of Meningeal Mast Cells and Trigeminal Neurons via MRGPRX2 Antagonism in Migraine

    Dual Inhibition of Meningeal Mast Cells and Trigeminal Neurons via MRGPRX2 Antagonism in Migraine Greg Dussor, PhD Professor, Department of Neuroscience The University of Texas at Dallas © Evommune, Inc.

  2. Slide 2: Disclosures

    Disclosures Last Two Years Potential COI Organization Advisory Boards • Delphian Therapeutics Speaker / Speakers Boards • n/a Consultant • Evommune Grant Support for Research • NIH, Evommune, Association of Migraine Disorders or Education • PAIN, PAIN Reports, Molecular Pain, Journal of Pain, Journa

  3. Slide 3: Mast Cells are Hypothesized to Contribute to Migraine

    Mast Cells are Hypothesized to Contribute to Migraine Dynamic Cross-Talk Between Anatomical Relevance Meningeal Mast Cells and • Abundant in meninges and perivascular spaces – regions Trigeminal Sensory Neurons innervated by trigeminal neurons Inflammatory Neuroimmune Communication Mediators • Trige

  4. Slide 4: MRGPRX2: Key Mediator of Interactions Between Mast Cells and Sensory Neurons in the Meninges

    MRGPRX2: Positioned as a Key Mediator of the Interactions Between Mast Cells and Sensory Neurons in the Meninges MRGPRX2 is Expressed on Both Meningeal Mast Cells Expression Confirmed in and Trigeminal Sensory Neurons Disease-Relevant Tissues Meninges Trigeminal Ganglia Pia Dura Mater Mater Trigemin

  5. Slide 5: MRGPRX2 Ligands Induce Migraine Attacks in Humans

    MRGPRX2 Ligands Induce Migraine Attacks in Humans MRGPRX2 Ligands are Associated PACAP, VIP, Substance P Infusion with Migraine All Induce Migraine-Like Headache Neuropeptides in Migraineurs Substance P Peptides PACAP 1-27 hormones PACAP 1-38 Protein / Peptide 100 Antimicrobial PAMP-12 VIP fragments

  6. Slide 6: PACAP Inhibition Achieves CGRP-Like Efficacy in Migraine Prophylaxis

    PACAP Inhibition Achieves CGRP-Like Efficacy in Migraine Prophylaxis Lundbeck’s Bocunebart Reduced Second Neuropeptide Axis Monthly Migraine Days by ~2 Validated in Migraine Prevention Bocunebart (IV) Placebo 0 PACAP is a key neuropeptide trigger Monthly Migraine Days of migraine attacks Mean Change

  7. Slide 7: Receptor(s) PACAP Engages to Induce Migraine Not Yet Clear

    Receptor(s) PACAP Engages to Induce Migraine Not Yet Clear PACAP May Be Triggering Migraine Through MRGPRX2 Relevant Clinical PACAP Tissue Validation PACAP Receptor Expression In Migraine? PAC1 Neurons1 VPAC1 Cranial Vessels Not X ? VPAC2 Neurons (?) evaluated Mast Cells MRGPRX2 Sensory Neurons TBD

  8. Slide 8: PACAP Causes Migraine-Like Behavior via MRGPRB2 as Primary Receptor in Mice

    PACAP Causes Migraine-Like Behavior via MRGPRB21 as Primary Receptor in vivo in Mice MRGPRX2 Ligand PACAP Knockout of MRGPRX21 Reduced Induces Headache in vivo PACAP-Induced Migraine Symptoms 1 PACAP injected directly onto Facial withdrawal threshold2 meninges of wild type and knockout models 2 Faci

  9. Slide 9: MRGPRX2 is Expressed in Human Sensory Neurons: Greater in TG

    MRGPRX2 is Expressed in Human Sensory Neurons: Greater in TG Targeting MRGPRX2 in Neurons Could Provide Greater Benefit Over Targeting Only in Mast Cells MRGPRX2 is Expressed by 25% MRGPRX2 is Expressed by >50% of DRG Neurons of TG Neurons 48.3% 41.6% 8.3% Dorsal root ganglia: 1.6% sensory neurons T

  10. Slide 10: EVO756 Potently Inhibits PACAP, Substance P, and VIP-Induced MRGPRX2 Activation in vitro

    EVO756: Small Molecule Potently (low nM) Inhibits PACAP, Substance P, and VIP-Induced MRGPRX2 Activation in vitro EVO756 Inhibits Migraine Relevant EVO756 Inhibits PACAP and SP-Induced Endogenous Ligands in X2-CHO Cells Primary Human Mast Cell Activation in vitro 120 CD107a CD63 PACAP 1-27 Concentra

  11. Slide 11: EVO756 Prevents Human DRG Sensory Neurons Activation

    EVO756 Prevents Human DRG Sensory Neurons Activation Targeting MRGPRX2 in Neurons Could Lead to Reduction in Neurogenic Inflammation and Itch/Pain Relief Functional Calcium Mobilization System Calcium Imaging Reveals that MRGPRX2 for Neuronal Activation in Neurons is Active, and Its Activity Can be

  12. Slide 12: EVO756 is Distributed in Migraine-Relevant Tissues

    EVO756 is Distributed in Migraine-Relevant Tissues Sensory Neurons and Mast Cells are Present in Tissues Critical for Migraine Pathophysiology With Perfusion 80 Dorsal Root Ganglia Trigeminal Ganglia Cranial Meninges (g tissue/mL plasma) 60 % EVO756 %EVO756 40 Skin:plasma Reference range 20 0 1 8 1

  13. Slide 13: MRGPRX2 Inhibition: a Promising New Direction in Migraine Therapy

    MRGPRX2 Inhibition: a Promising New Direction in Migraine Therapy EVO756 Interrupts the Migraine • Multiple migraine triggers converge on MRGPRX2 — PACAP, VIP, and Substance P are all MRGPRX2 Neuroimmune Circuit agonists Inflammatory • MRGPRX2 positioned at the neuroimmune interface Mediators — expr

  14. Slide 14: Acknowledgements

    Acknowledgements • Amanda Jacobson • Shiva Nematgorgani • Sreya Bagchi • Jane Brandon • Lorena Riol-Blanco • Keerthana Nataranjan • Ishwarya • Grant support from Sankaranarayanan Evommune to UT Dallas • Joseph Lesnak • Theodore Price 14 © Evommune, Inc.

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