Slide 1: Phase 1 Results for SEP-631, a Novel Oral MRGPRX2 NAM for Mast Cell-Driven Diseases
Exhibit 99.2 Phase 1 Results* for SEP-631, a Novel Oral Small Molecule MRGPRX2 Negative Allosteric Modulator (NAM) for Mast Cell-Driven Diseases March 2, 2026 Nasdaq: SEPN *Data presented at the 2026 American Academy of Allergy Asthma & Immunology (AAAAI) Annual Meeting © 2026 SEPTERNA
Slide 2: Forward-Looking Statements
Forward-Looking Statements This presentation contains express or implied forward‐ looking statements of Septerna, Inc. (the “Company,” “we,” or “our”) within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. All statements other than statements of historical facts cont
Slide 3: Agenda
Agenda • Septerna: Building a World-Class GPCR-Focused Biotechnology Company • SEP-631: Oral Small Molecule MRGPRX2 Negative Allosteric Modulator (NAM) • SEP-631: Phase 1 Healthy Subject Trial Results • Safety, Pharmacokinetics, and Pharmacodynamics (with Icatibant Skin Challenge) • SEP-631: Broad O
Slide 4: Septerna: Pioneering a New Era of GPCR Drug Discovery with Oral Small Molecules
Septerna: Pioneering a New Era of GPCR Drug Discovery with Oral Small Molecules • GPCR drug discovery has been concentrated to a small number of targets - our strategy is to unlock difficult-to-drug GPCRs ® • Our Native Complex Platform enables us to • Growing portfolio of clinical programs rapidly
Slide 5: Advancing a Deep Portfolio of Oral Small Molecule GPCR-Targeted Programs
Advancing a Deep Portfolio of Oral Small Molecule GPCR-Targeted Programs Wholly-Owned Programs Development Status Program / Target Therapeutic Area Discovery IND-enabling Phase 1 Phase 2 Mode of Action Indications / US Patient Population * Phase 1 initiation Anticipate Phase 1 Endocrinology SEP-479
Slide 6: SEP-631: Oral Small Molecule MRGPRX2 NAM
SEP-631: Oral Small Molecule MRGPRX2 NAM Targeting MRGPRX2 for Mast Cell-Driven Diseases © 2026 SEPTERNA
Slide 7: MRGPRX2 is a Key Regulator of Mast Cell Degranulation
MRGPRX2 is a Key Regulator of Mast Cell Degranulation Activated by Several Endogenous Ligands MRGPRX2 is activated by a host of endogenous agonists leading to IgE-independent mast cell degranulation • Include several neuropeptides and immune ligands Mast cell degranulation leads to release of mediat
Slide 8: Broad Opportunity for New Medicines Targeting Several Mast Cell-Driven Diseases
Broad Opportunity for New Medicines Targeting Several Mast Cell-Driven Diseases Mast cells are key mediators of allergic and inflammatory diseases • Reside in organ systems throughout the body Degranulation results in the release of an array of mediators which result in pain, itch, and inflammation
Slide 9: SEP-631: MRGPRX2 NAM with a Potentially Differentiated Profile
SEP-631: MRGPRX2 NAM with a Potentially Differentiated Profile for Mast Cell-Driven Diseases SEP-631 Induces a Structural Change in MRGPRX2 SEP-631 is a negative allosteric modulator (NAM) That Completely Closes the Agonist Binding Pocket • Binds to a novel allosteric site, distinct from the agonist
Slide 10: SEP-631 Inhibited MRGPRX2 Activation in Humanized Mouse Translational Model
SEP-631 Inhibited MRGPRX2 Activation in Humanized Mouse Translational Model Human MRGPRX2 Knock-in (KI) SEP-631 Potently Inhibited Skin Extravasation Mouse Model of Skin Extravasation Knock-in Mouse Cortistatin-14 (0.7 µg/ml) Icatibant (10 µg/ml) mMRGPRB2 KO hMRGPRX2 KI Treat with oral MRGPRX2 NAM (
Slide 11: SEP-631 Preclinical Data Supports Potential Best-in-Class Profile
SEP-631 Preclinical Data Supports Potential Best-in-Class Profile SEP-631 Preclinical Profile Subnanomolar binding affinity and slow off-rate kinetics Insurmountable negative allosteric modulator mechanism closes off agonist binding pocket • Inability to activate receptor despite presence of high do
Slide 12: First-in-Human Phase 1 Study of the Oral MRGPRX2 Antagonist SEP-631
First-in-Human, Proof-of-Mechanism Phase 1 Study of the Oral MRGPRX2 Antagonist SEP-631 © 2026 SEPTERNA
Slide 13: SEP-631 Phase 1 Study Design
SEP-631 Phase 1 Study Design A Phase 1, Double-Blind, Randomized, Placebo-Controlled, Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, and Food Effects of SEP-631 in Healthy Adult Volunteers Part A. SEP-631 PO single dose* Key endpoin
Slide 14: Safety: Single Dose Adverse Event Profile Comparable to Placebo
Safety: Single Dose Adverse Event Profile Comparable to Placebo • Rate of TEAEs with SEP-631 was comparable with placebo • No severe or serious events were reported • 2 AEs of mild transaminase elevations (<1.5x ULN) observed with SEP-631 were not related to dose, and at rates comparable to placebo
Slide 15: Safety: Multiple Dose Adverse Event Profile Comparable to Placebo
Safety: Multiple Dose Adverse Event Profile Comparable to Placebo • Rate of TEAEs with SEP-631 was comparable with placebo. • No severe or serious events were reported • One mild transaminase elevation (<1.5x ULN) observed with SEP-631 and one observed with placebo SEP-631 Multiple Dose (10 Days) Po
Slide 16: SEP-631 Pharmacokinetics: Dose-Proportional, Once Daily Dosing, No Food Effects
SEP-631 Pharmacokinetics: Dose-Proportional, Support Once Daily Dosing, and Without Food Effects • Approximately dose-proportional exposures were observed across the evaluated dose range • Elimination half-life of SEP-631 is approximately 24 hours, supporting once-daily (QD) dosing • SEP-631 with hi
Slide 17: Pharmacodynamics Assessed Using Icatibant Skin Challenge and AllergyScope Detector
Pharmacodynamics Assessed Using Icatibant Skin Challenge and AllergyScope Detector Forearm Intradermal Skin challenge performed at baseline (Day –1) and steady-state (Day 9) Injection Pattern following SEP-631 or placebo treatment Saline Histamine • Skin challenge agents: saline (injection control),
Slide 18: SEP-631 Inhibits Icatibant Wheal Formation in Dose-Dependent Manner
SEP-631 Inhibits Icatibant Wheal Formation in Dose-Dependent Manner to Complete Inhibition • SEP-631 completely inhibited icatibant 10 μg/mL-induced wheals at 10 mg QD, the lowest dose evaluated • SEP-631 inhibited icatibant 100 μg/mL-induced wheals in a dose-dependent manner, with near to complete
Slide 19: Phase 1 Results Support Further Development of SEP-631
Phase 1 Results Support Further Development of SEP-631 SEP-631 was well-tolerated across all studied doses Pharmacokinetic profile of SEP-631 supports once-daily oral dosing • Elimination half-life of SEP-631 is approximately 24 hours SEP-631 treatment resulted in robust inhibition of icatibant-indu
Slide 20: SEP-631: Broad Opportunity in Mast Cell-Driven Diseases
SEP-631: Broad Opportunity in Mast Cell-Driven Diseases © 2026 SEPTERNA
Slide 21: SEP-631 Preclinical Profile Translated Well to Phase 1 Clinical Trial Results
SEP-631 Preclinical Profile Translated Well to Phase 1 Clinical Trial Results Translation SEP-631 Preclinical Profile Robust SEP-631 Phase 1 Results • Subnanomolar binding affinity Target Coverage • Estimated high receptor occupancy (>99%) • Slow receptor off-rate kinetics • Confirmed QD oral dosing
Slide 22: SEP-631: Initial Phase 2 Development Strategy
SEP-631: Initial Phase 2 Development Strategy Since the skin has the highest level of MRGPRX2 expression on mast cells, plan to rapidly advance into Chronic Urticaria studies • Targeting initiation of a Phase 2b Chronic Spontaneous Urticaria study in 2H 2026 • Pursue open-label Chronic Inducible Urt
Slide 23: Chronic Spontaneous Urticaria (CSU): High Disease Burden, Large Patient Population
Chronic Spontaneous Urticaria (CSU): High Disease Burden, Large Patient Population • CSU is an undertreated dermatology condition characterized by CSU Skin Wheals and Angioedema itchy and painful wheals and angioedema 1 • Significant burden of disease; patients experience : Disease Burden % CSU Pati
Slide 24: Plan to Initiate Phase 2b Dose-Ranging CSU Study in 2H 2026
Plan to Initiate Phase 2b Dose-Ranging Chronic Spontaneous Urticaria Study in 2H 2026 • Long-term GLP toxicology studies in rats and dogs to be completed by mid-year 2026 • Planned global, randomized, double-blind, placebo-controlled study to evaluate safety and exploratory efficacy of SEP-631 in CS
Slide 25: Exploring Opportunities for SEP-631 in Additional Indications with High Unmet Need
Exploring Opportunities for SEP-631 in Additional Indications with High Unmet Need • Indications characterized by mast cells playing a central role in disease pathology and evidence of MRGPRX2 expression on tissue-resident mast cells • Indications cover breadth of target organs and have different pa
Slide 26: Building a World-Class GPCR-Focused Biotechnology Company
Building a World-Class GPCR-Focused Biotechnology Company © 2026 SEPTERNA
Slide 27: Septerna: Building a World-Class GPCR-Focused Biotechnology Company
Septerna: Building a World-Class GPCR-Focused Biotechnology Company ® • SEP-631 Phase 1 results provides clear validation of Septerna’s Native Complex Platform • Identification of novel binding pockets to mechanistically modulate GPCRs in therapeutically meaningful ways including unlocking new modes
Slide 28: Pioneering a New Era of GPCR Drug Discovery
Pioneering a New Era of GPCR Drug Discovery © 2026 SEPTERNA