Septerna, Inc. · NASDAQ:SEPN

Septerna — Investor Presentation (November 2026)

37 slides from Septerna's investor presentation, Nov 4, 2026

  1. Slide 1: Pioneering a New Era of GPCR Drug Discovery

    Exhibit 99.2 Pioneering a New Era of GPCR Drug Discovery Corporate Presentation November 2026 Nasdaq: SEPN © 2026 SEPTERNA

  2. 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

  3. Slide 3: Lead Programs: Pioneering a New Era of GPCR Drug Discovery

    Lead Programs SEP-479 PTH1R Agonist: Potential first-in-class oral Septerna: Pioneering a New small molecule for hypoparathyroidism; Phase 1 in Era of GPCR Drug Discovery healthy volunteers ongoing with SAD/MAD data anticipated in Q1 2027 with Oral Small Molecules SEP-204 TSHR NAM: Potential disease

  4. Slide 4: GPCR Drug Discovery Success Concentrated in 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

  5. 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 Platf

  6. 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 Endocrinology SEP-479 (PTH1R) Anticipate Phase 1 data in Q1 2027 Hypoparathyroidism Ag

  7. Slide 7: SEP-479: Oral Small Molecule PTH1R Agonist for Hypoparathyroidism

    SEP-479: Oral Small Molecule PTH1R Agonist Targeting PTH1R for Hypoparathyroidism © 2026 SEPTERNA

  8. Slide 8: Hypoparathyroidism: Significant Unmet Need for an Oral PTH Replacement

    Hypoparathyroidism: Significant Unmet Need for an Oral PTH Replacement PTH: Master Regulator of Blood Calcium 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 compli

  9. 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

  10. Slide 10: SEP-479: Pharmacologic Responses Similar to PTH Peptide in Cell-Based Assays

    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 RANKL Osteocalcin Osteoprotegerin 8 1.5

  11. Slide 11: SEP-479 Normalized Serum Calcium and Phosphate in Rat 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 2+ Serum Ca Levels Serum Phosphate Levels Rat Surgery to remove parathyroid glands Decreased se

  12. Slide 12: SEP-479 Improved Renal Mineral Homeostasis and Engaged Bone Remodeling

    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

  13. Slide 13: SEP-479 Lowered Endogenous PTH and Increased Serum Calcium in Monkeys

    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

  14. 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

  15. 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 SEP-479 : placebo Study design: Single PK 2+ # cohorts TBD ascending dose PTH, Ca SEP-479 x 1 Other biomarkers • Randomized, placebo-controlled, single ascending dose SEP-479 x 1 (SAD

  16. Slide 16: SEP-204: Oral Small Molecule TSHR NAM for Graves' Disease and TED

    SEP-204: Oral Small Molecule TSHR NAM Targeting TSHR for Graves’ Disease and TED © 2026 SEPTERNA

  17. Slide 17: Graves' Disease and TED: Unmet Need for a Disease-Modifying Therapy

    Graves’ Disease and Thyroid Eye Disease (TED): Unmet Need for a Disease-Modifying Therapy Graves’ Disease & TED Share Pathophysiology: • Autoantibodies activate TSHR in thyroid gland and in orbital fibroblasts behind the eyes Graves’ Disease • >2M patients in US; no new treatments approved in decade

  18. Slide 18: Spectrum of TSHR Autoimmune Disease Manifestations and Unmet Needs

    Graves’ Disease and TED: Spectrum of TSHR Autoimmune Disease Manifestations and Unmet Needs Significant unmet need for a new medicine that addresses the full spectrum of Graves’ disease and co-morbid TED Graves’ Disease Graves’ + Subclinical-to-Mild TED Graves’ + Moderate-to-Severe TED • Alternative

  19. Slide 19: SEP-204: Oral Small Molecule TSHR NAM Development Candidate

    SEP-204: Oral Small Molecule TSHR Negative Allosteric Modulator (NAM) Development Candidate TSHR undergoes a large conformational change when activated; SEP-204 SEP-204: Development Candidate prevents activation and signaling Potent oral small molecule TSHR NAM Demonstrated inhibition of thyroid sti

  20. Slide 20: TSHR Inhibition: Neuroendocrine Feedback Expected to Increase TSH

    TSHR Inhibition: Neuroendocrine Feedback Expected to Lead to Increases in TSH and Decreases in Thyroid Hormone Levels Hypothalamic-Pituitary- Anticipated Effects of TSHR NAM in Healthy Animals and Graves’ Models Thyroid Feedback Axis © 2026 SEPTERNA 20

  21. Slide 21: SEP-204 Increased TSH and Decreased T4 in Healthy Rats

    SEP-204 Increased TSH and Decreased Thyroid Hormone T4 in Healthy Rat Pharmacodynamic Study SEP-204 (PO BID x 5 days) ↑ TSH ↓ T4 Rat SEP-204 PK/PD: TSH Levels Thyroid Hormone T4 Levels TSH & T4 vs. Drug Exposure 100 1.5 100 10 1.0 10 TSH Total T4 1 0.5 1 0.1 0.1 0.0 Vehicle 1 3 10 Vehicle 1 3 10 SEP

  22. Slide 22: SEP-204 in a Rat TSAb Challenge Model

    SEP-204 Increased TSH and Normalized or Decreased Thyroid Hormone Levels in a Rat TSAb Challenge Model Total T4 Thyroid Hormone Levels over Time M22 (TSAb) 8 SEP-204 ↑ T4 Normalized or M22 SEP-204 ↓ TSH Decreased T4 single dose Rat 6 4 Rat Thyroid Stimulating Antibody (TSAb) Challenge Model 2 • Sing

  23. Slide 23: SEP-204 Reversed Graves' Disease and TED Manifestations in Mouse Model

    SEP-204 Reversed Manifestations of Graves’ Disease and TED in a TSAb-Driven Mouse Model SEP-204 ↑ Thyroid Hormones M22 (TSAb) M22 (TSAb) Reversal of Thyroid and ↑ Thyroid Size Eye Manifestations 6 weeks 2 weeks ↑ Eye Proptosis Mouse Thyroid Histology and Volume Orbital Proptosis Mouse Model of Grave

  24. Slide 24: SEP-204 Preclinical Profile Supports Advancement into Phase 1

    SEP-204 Preclinical Profile Supports Advancement into Phase 1 Potent oral small molecule TSHR NAM • Demonstrated inhibition of TSAb activation of TSHR in human thyrocyte cell assays • Restored normal T4 levels and decreased thyroid enlargement and orbital proptosis in Graves’ disease animal models •

  25. Slide 25: SEP-631: Oral Small Molecule MRGPRX2 NAM for Mast Cell-Driven Diseases

    SEP-631: Oral Small Molecule MRGPRX2 NAM Targeting MRGPRX2 for Mast Cell-Driven Diseases © 2026 SEPTERNA

  26. Slide 26: 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

  27. Slide 27: 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

  28. Slide 28: SEP-631 Phase 1 SAD/MAD Demonstrated Safety and Robust Pharmacodynamics

    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) Skin Challenge (Pre-dose) Forearm Intradermal Key endpoints Single Randomization 400 mg Injection Pattern 300 mg 6:2 ascending 200 mg (SEP-631:placebo

  29. Slide 29: 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

  30. Slide 30: SEP-631 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

  31. Slide 31: 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

  32. Slide 32: Metabolic Programs: Oral Small Molecules Targeting GLP-1R, GIPR, GCGR

    Metabolic Programs Oral Small Molecule Programs Targeting GLP-1R, GIPR, GCGR and Other Targets for Obesity, Diabetes, and Other Cardiometabolic Diseases © 2026 SEPTERNA

  33. Slide 33: Collaboration with Novo for Oral Small Molecules for Metabolic Diseases

    Collaboration with Novo 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 agonists Poten

  34. Slide 34: Building a World-Class GPCR-Focused Biotechnology Company

    Building a World-Class GPCR-Focused Biotechnology Company © 2026 SEPTERNA

  35. Slide 35: Proven Leaders in GPCR Drug Development and Company Building

    Proven Leaders in GPCR Drug Development and Company Building Senior Leadership Dan Long, DPhil Jeff Finer, MD PhD Liz Bhatt, MS MBA Rajiv Patni, MD Gil Labrucherie, CFA JD Uwe Klein, PhD Samira Shaikhly Mark Wilson, JD CEO President & COO CMO CFO SVP Biological Sciences SVP Drug Discovery CPO CLO Bo

  36. Slide 36: Septerna: Pioneering a New Era of GPCR Drug Discovery

    Septerna: Pioneering a New Era of GPCR Drug Discovery Wholly-Owned Programs Development Status • Portfolio of oral small molecule GPCR- Program / Target targeted programs Discovery IND-enabling Phase 1 Phase 2 Mode of Action SEP-479 (PTH1R) Anticipate Phase 1 • Multi-product pipeline, each with a mu

  37. Slide 37: Pioneering a New Era of GPCR Drug Discovery

    Pioneering a New Era of GPCR Drug Discovery © 2026 SEPTERNA

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