Slide 1: Results from a Phase 1 Study
Results from a Phase 1 Study EVO756, an oral MRGPRX2 antagonist, is well-tolerated and demonstrates target engagement Authors: Sarbjit S. Saini, MD1, Kelly Devine, RN, BSN, CCRP1, Tahira Mirza, MBBS, CCRP1, Kristin L. Chichester, MS1, Janice Drew2, MPH, Polina Bukshpun2, Kelsey Santisteban2, Dan Bur
Slide 2: Conflict of Interest Disclosure
Conflict of Interest Disclosure q I have the following, real or perceived direct or indirect conflicts of interest that relate to this presentation: Type of affiliation / financial interest Name of commercial company Receipt of grants/research supports: NIH, Novartis, Escient, Allakos, Jasper Allako
Slide 3: MRGPRX2-dependent Mast Cell-Neuron interactions regulate feedback mechanisms in CSU
MRGPRX2-dependent Mast Cell-Neuron interactions regulate multiple feedback mechanisms driving pathophysiological processes in CSU Targeting MRGPRX2 may improve CSU signs and symptoms MRGPRX2: Nexus for MC/neuron MRGPRX2-dependent feedback loops amplify neuroinflammation pathology activation by multi
Slide 4: MRGPRX2's Potential Role in CSU
MRGPRX2’s Potential Role in CSU Long recognized MRGPRX2 identified Increased X2 Increased skin 48/80 skin reactivity as receptor on skin expression noted reactivity with X2 increased in MCs for 48/80 and in skin biopsies of ligand testing CSU patients other ligands CSU subjects (icatibant) Bedard JA
Slide 5: EVO756 is an Oral MRGPRX2 Antagonist Targeted for CSU
EVO756 is an Oral MRGPRX2 Antagonist Targeted for CSU Phase 1 Study Design: Single and Multiple Ascending Dose Cohorts with EVO756 PART A: SAD Dosing PART B: MAD Dosing N= 55 (41 active/14 placebo) N=77 (58 active/19 placebo) Cohort A7 500 mg Cohort B5 √ Skin Challenge Cohort A6 500 mg QD 240 mg Coh
Slide 6: Safety – Single Ascending Dose Cohorts
Safety – Single Ascending Dose Cohorts Placebo Cohort A1 Cohort A2 Cohort A3 Cohort A4 Cohort A5 Cohort A6 Cohort A7 (Pooled) 1 mg 3 mg 10 mg 30 mg 100 mg 240 mg 500 mg n 14 6 6 5 6 6 6 6 Total Number of TEAEs 8 2 1 2 3 3 3 3 Total Number of Subjects 6 (42.9%) 2 (33.3%) 1 (16.7%) 2 (40%) 2 (33.3%) 2
Slide 7: Safety – Multiple Ascending Dose Cohorts (14 days)
Safety – Multiple Ascending Dose Cohorts (14 days) Placebo Cohort B1 Cohort B2 Cohort B3 Cohort B4 Cohort B5 (Pooled) 10 mg BID 30 mg BID 100 mg BID 240 mg BID 500 mg QD n 19 11 12 12 11 12 Total Number of TEAEs 13 8 4 14 10 10 Total Number of Subjects 8 (42.1%) 4 (36.4%) 4 (33.3%) 5 (41.7%) 2 (18.2
Slide 8: Multiple Dose Pharmacokinetics (14 Days)
Multiple Dose Pharmacokinetics (14 Days) Half-life of 8-12 hours supports once and twice daily dosing regimens Log-Linear Plots of Mean EVO756 Plasma Concentrations vs Time 100000 24 Hour 10000 21x IC90 Concentration (ng/mL) 1000 1.2x IC90 IC90 100 10 Cohort CohortB1B1(10 (10mg, mgN=11) BID, N=11) C
Slide 9: Proof of Concept & Target Engagement for Chronic Urticaria
Proof of Concept & Target Engagement for Chronic Urticaria Skin Icatibant Mast Cell Blood Vessel Subcutaneous Mast Cell Increased Vascular Delivery of Icatibant Activation Permeability Leads to Saline Icatibant Localized Swelling Baseline/Pre-Dose Day 14: Challenge Repeated Icatibant Injections H H
Slide 10: Icatibant Skin Challenge Assesses EVO756 Target Engagement
Icatibant Skin Challenge Assesses EVO756 Target Engagement EVO756-HV001 Mean Wheal Size (mm) (Dynamic Range of 0-4 mm) 14 • In vitro pharmacology of 12 Icatibant is comparable to that of all MRGPRX2 10 ligands tested 4 mm 8 2 mm • Highly consistent and 6 reproducible wheals formed with Icatibant at
Slide 11: EVO756 Robustly Decreases Icatibant Wheal Size in a Dose-Dependent Manner
EVO756 Robustly Decreases Icatibant Wheal Size in a Dose-Dependent Manner Icatibant: 10 µg/mL Icatibant: 100 µg/mL 13 13 * ** ** 12 12 11 11 Mean Wheal Size (mm) Mean Wheal Size (mm) * * -1.8 mm 10 ** 10 -2.5 mm -3 mm 9 9 -2 mm -1.7 mm p < 0.0001 8 -2.1 mm 8 7 Saline 7 Saline p < 0.0001 p < 0.0001 p
Slide 12: EVO756 Phase 1 Data Support Advancement to Phase 2
EVO756 Phase 1 Data Support Advancement to Phase 2 • EVO756 is well tolerated across all doses • Pharmacokinetics support once and twice daily dosing • Clear target engagement • Further evaluation in patients with active CSU and CIndU is warranted 12