Slide 1: Pioneering a New Era of GPCR Drug Discovery
Nasdaq: SEPN Pioneering a New Era of GPCR Drug Discovery September 2025 Corporate Presentation Exhibit 99.1
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: 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 Native Complex Platform™ designed to unlock the full potential of GPCR therapies Iterative structure-based drug design to rapidly optimize and validate programs in animal models Portfolio strategy to drive value creation
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 >70% of GPCR drugs target 6 small subfamilies of GPCRs ~1/3 of all FDA-approved drugs (~500 approve
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 G protein Lipid Bilayer Lig
Slide 6: Native Complex Platform is a Highly Efficient Platform for GPCR Structure-Based Drug Design
Native Complex Platform™ is a Highly Efficient Platform for GPCR Structure-Based Drug Design New Small Molecule Ligand New Ligand-Bound GPCR Structure ~1-2 weeks Native Complex Cryo-EM Structure-Based Design Rapid Iterative Cycle Apo (no ligand) Agonist Positive Allosteric Modulator Antagonist Negat
Slide 7: 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 a Program / Target Mode of Action Therapeutic Area Indications / US Patient Population Discovery IND-enabling Phase 1 Phase 2 SEP-479 (PTH1R) Agonist Endocrinology Hypoparathyroidism: ~7
Slide 8: PTH1R Agonist Program
PTH1R Agonist Program Oral Small Molecule Targeting PTH1R for Hypoparathyroidism
Slide 9: 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 ~70K patients in US; ~140K patients in EU Challenging patient symptoms Muscle cramps, tingling, brain fog Life-threatening complications: cardiac arrhythmias, seizures Inadeq
Slide 10: Native Complex Platform Identified Broad Portfolio of Distinct Agonists for PTH1R
Native Complex Platform™ Identified Broad Portfolio of Distinct Agonists for PTH1R (a Historically Challenging Small Molecule Target) Multiple PTH1R agonists with distinct binding sites Native Complex Hit Identification Multiple PTH1R agonist series optimized in parallel Native Complex Structure-Bas
Slide 11: SEP-786: First Clinical PTH1R Agonist Discontinued in Phase 1 Due to Unanticipated Events
SEP-786: First Clinical PTH1R Agonist Discontinued in Phase 1 Due to Unanticipated Events SEP-786 Phase 1 SAD/MAD trial in healthy volunteers discontinued 2 unanticipated severe (Grade 3) events of elevated unconjugated bilirubin levels in MAD Both events were reversible and without liver injury (no
Slide 12: SEP-479: A Potent, Selective PTH1R Agonist Normalized Serum Calcium and Phosphate
SEP-479: A Potent, Selective PTH1R Agonist Normalized Serum Calcium and Phosphate in Hypoparathyroidism Animal Model Surgery to remove parathyroid glands Rat Decreased serum calcium (hypocalcemia) Oral small molecule PTH1R agonist Normalize serum calcium Rat surgical model of hypoparathyroidism PO =
Slide 13: SEP-479: Preclinical Studies Demonstrated Favorable Pharmacokinetic and Pharmacodynamic Profiles
SEP-479: Preclinical Studies Demonstrated Favorable Pharmacokinetic and Pharmacodynamic Profiles SEP-479 Parameter Mouse Rat Dog Cyno Oral Bioavailability (%F) 90 93 77 56 PO Half-life (hr) 7.2 14 39 17 Predicted Human Half-life 43-87 hr SEP-786 Mouse Rat Dog Cyno 54 26-50 40-60 44 4.6 4-8 5-7 8.2 P
Slide 14: SEP-479: Preclinical Development and Next Steps
SEP-479: Preclinical Development and Next Steps SEP-479 Safety Studies No significant inhibition of UGT1A1 or other transporters observed (studied in parallel with SEP-786 investigation) No hyperbilirubinemia observed in all non-clinical studies to date, including in a 7-day cynomolgus monkey study
Slide 15: SEP-631: Oral Small Molecule MRGPRX2 NAM
SEP-631: Oral Small Molecule MRGPRX2 NAM Targeting MRGPRX2 for Mast Cell Disorders, Including CSU
Slide 16: MRGPRX2: Emerging Target for Mast Cell-Driven Diseases
MRGPRX2: Emerging Target for Mast Cell-Driven Diseases MRGPRX2 Highly and uniquely expressed on mast cells Distinct from IgE / allergen pathway Multiple endogenous agonists Mast Cell-Driven Diseases CSU, atopic dermatitis, allergic asthma, and others CSU: Significant Unmet Need ~1.5 million patients
Slide 17: SEP-631: Potent Oral Small Molecule MRGPRX2 NAM
SEP-631: Potent Oral Small Molecule MRGPRX2 NAM Designed to Stop MRGPRX2-Mediated Mast Cell Degranulation SEP-631 potently inhibited activation of MRGPRX2 by a range of endogenous agonists in vitro SEP-631 blocked IP1 accumulation in HEK293 cells expressing MRGPRX2 in response to multiple clinically
Slide 18: SEP-631 Inhibited MRGPRX2 Activation in Translational Models
SEP-631 Inhibited MRGPRX2 Activation in Translational Models SEP-631 Potently Inhibited Skin Extravasation in MRGPRX2 Knock-in Mouse Model Treat with oral MRGPRX2 NAM (SEP-631) or vehicle Administer Evans Blue dye Measure extravasation of dye into skin Extravasation (no MRGPRX2 inhibition) No extrav
Slide 19: SEP-631: Investigational MRGPRX2 NAM with Potentially Differentiated Profile
SEP-631: Investigational MRGPRX2 NAM with Potentially Differentiated Profile Key Criteria for Advancing Development SEP-631 High Potency Observed in multiple functional and binding assays Broad Inhibition Long residence time and insurmountable inhibition of multiple endogenous agonists Good Oral PK
Slide 20: SEP-631: Phase 1 Study in Healthy Volunteers Has Initiated
SEP-631: Phase 1 Study in Healthy Volunteers Has Initiated Goal: Evaluate the safety, tolerability, PK and PD of oral SEP-631 in healthy adult volunteers Initial SAD/MAD data anticipated in 1H 2026 Study details: Randomized, placebo-controlled, single ascending dose (SAD) and multiple ascending dose
Slide 21: TSHR NAM Program
TSHR NAM Program Oral Small Molecule Targeting TSHR for Graves’ Disease and TED
Slide 22: No Disease-Modifying Therapies for Graves' Disease and Thyroid Eye Disease
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 iodine,
Slide 23: Small Molecule TSHR NAM Inhibited Patient-Derived Autoantibody Activation of Primary Orbital Fibroblasts
Small Molecule TSHR NAM Inhibited Patient-Derived Autoantibody Activation of Primary Orbital Fibroblasts Selective TSHR NAMs Blocked activation of TSHR by patient-derived autoantibodies Insurmountable NAM profiles Preclinical Leads Inhibited Diverse Patient Autoantibodies Orbital fibroblasts and ser
Slide 24: Oral Small Molecule TSHR NAMs Reversed Symptoms in Novel Graves' Disease Model
Oral Small Molecule TSHR NAMs Reversed Symptoms in Novel Graves’ Disease Model Agonist mAb + Vehicle Agonist mAb + SP-1351 Isotype mAb control + Vehicle TSHR Activating Antibody Mouse Thyroid Hormone Levels Thyroid Size Eye Proptosis (bulging) TSHR Activating Ab +TSHR NAM Reversal of Thyroid a
Slide 25: Metabolic Programs
Metabolic Programs Oral Small Molecule Programs Targeting GLP-1R, GIPR, GCGR and Other Targets for Obesity, Diabetes, and Other Cardiometabolic Diseases
Slide 26: Collaboration with Novo Nordisk for Oral Small Molecules for Metabolic Diseases
Collaboration Objective: discover, develop and commercialize multiple novel mono-, dual-, or triple-acting oral small molecule drug candidates directed to obesity, type 2 diabetes and other cardiometabolic diseases Septerna and Novo commenced four initial R&D programs targeting five GPCRs Includes G
Slide 27: Building a World-Class GPCR-Focused Biotechnology Company
Building a World-Class GPCR-Focused Biotechnology Company
Slide 28: Proven Leaders in GPCR Drug Development and Company Building
Proven Leaders in GPCR Drug Development and Company Building Senior Leadership Jeff Finer, MD PhD CEO Liz Bhatt, MS MBA President & COO Gil Labrucherie, CFA JD CFO Samira Shaikhly CPO Jae Kim, MD CMO Uwe Klein, PhD SVP Biological Sciences Dan Long, DPhil SVP Drug Discovery Board of Directors Jeff Fi
Slide 29: Septerna: Pioneering a New Era of GPCR Drug Discovery
Septerna: Pioneering a New Era of GPCR Drug Discovery Portfolio of oral small molecule GPCR-targeted programs Multi-product pipeline, each with a multi-billion $ market opportunity Native Complex Platform™ drives rapid compound identification and portfolio expansion Well-capitalized with updated cas
Slide 30: Pioneering a New Era of GPCR Drug Discovery
Pioneering a New Era of GPCR Drug Discovery