Slide 1: Pioneering a New Era of GPCR Drug Discovery
Pioneering a New Era of GPCR Drug Discovery Corporate Presentation August 2026 Nasdaq: SEPN © 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 conta
Slide 3: Lead Programs
Lead Programs Septerna: Pioneering a New SEP-479 PTH1R Agonist: Potential first-in-class oral Era of GPCR Drug Discovery small molecule for hypoparathyroidism; Phase 1 in with Oral Small Molecules healthy volunteers initiated with SAD/MAD data anticipated in Q1 2027 Native Complex Platform® designed
Slide 4: GPCR Drug Discovery Success Has Been Highly Concentrated to a Small Fraction of GPCRs
GPCR Drug Discovery Success Has Been Highly Concentrated to a Small Fraction of GPCRs Historically productive target class, yet substantial untapped opportunity to expand the number of druggable GPCRs ~1/3 of all FDA-approved drugs (~500 approved products) target GPCRs >70% of GPCR drugs target 6 sm
Slide 5: Proprietary Native Complex Platform
Proprietary Native Complex Platform ® Today’s GPCR Drug Discovery Challenge • Several new small molecule drug discovery technologies have largely been inaccessible to GPCRs • Inability to isolate fully functional GPCR proteins significantly limits use of modern discovery tools Native Complex Platfor
Slide 6: 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 SEP-479 (PTH1R) Endocrinology Anticipate Phase 1 Hypoparathyroidism data in Q1 2027 Ag
Slide 7: SEP-479: Oral Small Molecule PTH1R Agonist
SEP-479: Oral Small Molecule PTH1R Agonist Targeting PTH1R for Hypoparathyroidism © 2026 SEPTERNA
Slide 8: Hypoparathyroidism: Significant Unmet Need for an Oral PTH Replacement
Hypoparathyroidism: Significant Unmet Need for an Oral PTH Replacement Hypoparathyroidism: Low PTH leads to low blood calcium PTH: Master Regulator of Blood Calcium • ~70K patients in US; ~140K patients in EU Challenging patient symptoms • Muscle cramps, tingling, brain fog • Life-threatening compli
Slide 9: SEP-479: Discovered with Native Complex Platform as Potent Oral PTH1R Agonist
SEP-479: Discovered with Native Complex Platform ® as Potent Oral PTH1R Agonist for Hypoparathyroidism Native Complex Hit Identification and Structure-Based Optimization SEP-479: Clinical Candidate Multiple PTH1R agonists with distinct binding sites identified and optimized in parallel to candidate
Slide 10: SEP-479: A Potent PTH1R Agonist Demonstrated Pharmacologic Responses Similar to PTH peptide
SEP-479: A Potent PTH1R Agonist Demonstrated Pharmacologic Responses Similar to PTH peptide in Cell-Based Assays Gene expression analysis comparing SEP-479 to PTH (1-34) in bone cell line demonstrated similar PTH1R- mediated pharmacologic responses Sclerostin Osteocalcin 8 RANKL Osteoprotegerin 1.5
Slide 11: SEP-479 Normalized Serum Calcium and Phosphate in Rat Hypoparathyroidism Model
SEP-479 Normalized Serum Calcium and Phosphate in Rat Hypoparathyroidism Model Rat surgical model of SEP-479: 28-day Oral QD Dosing hypoparathyroidism Sustained Normalization of Sustained Normalization of Serum Ca2+ Levels Serum Phosphate Levels Rat Surgery to remove parathyroid glands Decreased ser
Slide 12: SEP-479 Improved Renal Mineral Homeostasis and Engaged Bone Remodeling in Rat Model
SEP-479 Improved Renal Mineral Homeostasis and Engaged Bone Remodeling in Rat Hypoparathyroidism Model SEP-479 demonstrated PTH-like renal SEP-479 demonstrated PTH-like bone remodeling effects: pharmacology profile: • Decreased bone mineral density, increased CTX (serum bone catabolic marker) • Decr
Slide 13: SEP-479 Lowered Endogenous PTH and Increased Serum Calcium In Healthy Cynomolgus Monkey
SEP-479 Lowered Endogenous PTH and Increased Serum Calcium In Healthy Cynomolgus Monkey Pharmacodynamic Study In healthy animals (and humans) with normal parathyroid gland function: • Treatment with PTH agonists leads to rapid suppression of endogenous PTH secretion to maintain normal calcium levels
Slide 14: SEP-479 Preclinical Profile Supported Advancement into Phase 1
SEP-479 Preclinical Profile Supported Advancement into Phase 1 Potent oral small molecule PTH1R agonist • Demonstrated effects comparable to PTH peptides in cell-based assays and in vivo models Pharmacokinetic studies • Demonstrated high oral bioavailability and long half-life following oral dosing
Slide 15: SEP-479 Phase 1 Study in Healthy Volunteers is in Progress
SEP-479 Phase 1 Study in Healthy Volunteers is in Progress Endpoints SEP-479 x 1 Randomization Safety / tolerability Study design: Single SEP-479 : placebo PK ascending dose # cohorts TBD PTH, Ca2+ SEP-479 x 1 Other biomarkers • Randomized, placebo-controlled, single ascending dose SEP-479 x 1 (SAD)
Slide 16: SEP-631: Oral Small Molecule MRGPRX2 NAM
SEP-631: Oral Small Molecule MRGPRX2 NAM Targeting MRGPRX2 for Mast Cell-Driven Diseases © 2026 SEPTERNA
Slide 17: 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 18: 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 is a negative allosteric modulator (NAM) SEP-631 Induces a Structural Change in MRGPRX2 That Completely Closes the Agonist Binding Pocket • Binds to a novel allosteric site, distinct from the agonist
Slide 19: SEP-631 Phase 1 SAD / MAD Demonstrated Safety, Robust Pharmacodynamics, and PK
SEP-631 Phase 1 SAD / MAD Demonstrated Safety, Robust Pharmacodynamics, and PK to Support Once-Daily Oral Dosing Part A. SEP-631 PO single dose (SAD) Key endpoints Skin Challenge (Pre-dose) Forearm Intradermal Sing le Randomization 400 mg ascending 6:2 300 mg Injection Pattern (SE P-631 :pla ceb o)
Slide 20: SEP-631 Inhibited Icatibant Wheal Formation in Dose-Dependent Manner
SEP-631 Inhibited 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 21: SEP-631 Preclinical and Phase 1 Data Supports Potential Best-in-Class Profile
SEP-631 Preclinical and Phase 1 Data Supports Potential Best-in-Class Profile Full inhibition of Oral once-daily tablet Potential to translate into best-in-class MRGPRX2 activation + and clean safety profile efficacy for multiple disease indications NAM mechanism provides broad insurmountable MRGPRX
Slide 22: SEP-631: Clinical Development Strategy
SEP-631: Clinical Development Strategy Broad opportunity across a range of allergic and inflammatory diseases where mast cells are implicated in disease pathophysiology Near-Term Strategy: Explore opportunities for SEP-631 in multiple indications with capital-efficient and right-sized signal-finding
Slide 23: TSHR NAM Program
TSHR NAM Program Oral Small Molecule Targeting TSHR for Graves’ Disease and TED © 2026 SEPTERNA
Slide 24: No Disease-Modifying Therapies for Graves' Disease and Thyroid Eye Disease (TED)
No Disease-Modifying Therapies for Graves’ Disease and Thyroid Eye Disease (TED) Graves’ Disease & TED Pathophysiology: • Autoantibodies activate TSHR in thyroid gland and in orbital fibroblasts behind the eyes Graves’ Disease • >2M patients in US • Standard-of-care: antithyroid drugs, radioactive i
Slide 25: Oral Small Molecule TSHR NAMs Reversed Symptoms in Novel Graves' Disease Model
Oral Small Molecule TSHR NAMs Reversed Symptoms in Novel Graves’ Disease Model • Selective TSHR NAMs TSHR Activating TSHR Activating Ab Antibody Thyroid Hormone Levels +TSHR NAM Reversal of Thyroid and • Blocked activation of TSHR by Thyroid Size Eye Manifestations Eye Proptosis (bulging) pati
Slide 26: Metabolic Programs
Metabolic Programs Oral Small Molecule Programs Targeting GLP-1R, GIPR, GCGR and Other Targets for Obesity, Diabetes, and Other Cardiometabolic Diseases © 2026 SEPTERNA
Slide 27: Collaboration with Novo Nordisk for Oral Small Molecules for Metabolic Diseases
Collaboration with Novo Nordisk for Oral Small Molecules for Metabolic Diseases Septerna and Novo commenced four initial R&D programs targeting five GPCRs • Includes GLP-1, GIP and glucagon receptors • Collaboration includes Septerna’s preclinical, selective, oral, small molecule GIP receptor agonis
Slide 28: Building a World-Class GPCR-Focused Biotechnology Company
Building a World-Class GPCR-Focused Biotechnology Company © 2026 SEPTERNA
Slide 29: Proven Leaders in GPCR Drug Development and Company Building
Proven Leaders in GPCR Drug Development and Company Building Senior Leadership Jeff Finer, MD PhD Liz Bhatt, MS MBA Gil Labrucherie, CFA JD Uwe Klein, PhD Dan Long, DPhil Samira Shaikhly Mark Wilson, JD CEO President & COO CFO SVP Biological Sciences SVP Drug Discovery CPO CLO Board of Directors Aca
Slide 30: Septerna: Pioneering a New Era of GPCR Drug Discovery
Septerna: Pioneering a New Era of GPCR Drug Discovery • Portfolio of oral small molecule GPCR- Wholly-Owned Programs Development Status targeted programs Program / Target Discovery IND-enabling Phase 1 Phase 2 Mode of Action • Multi-product pipeline, each with a multi- SEP-479 (PTH1R) Anticipate Pha
Slide 31: Pioneering a New Era of GPCR Drug Discovery
Pioneering a New Era of GPCR Drug Discovery © 2026 SEPTERNA