SEPN Corporate presentation

Page 1

Nasdaq: SEPN Pioneering a New Era of GPCR Drug Discovery January 2026 Corporate Presentation

Page 2

2© 2026 SEPTERNA 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 contained in this presentation, including statements regarding our business strategy, plans, estimated R&D program milestones and objectives of management are forward-looking statements. Such forward-looking statements include, but are not limited to, statements regarding: the continued advancement of our PTH1R agonist program, including the planned initiation of a Phase 1 clinical trial for SEP-479 in the first half of 2026 subject to successful completion of drug product manufacturing and regulatory submissions; the continued advancement of SEP-631, including the potential of SEP-631 to provide a convenient oral treatment option for patients with mast cell-driven diseases (e.g., CSU); the role of MRGPRX2 in mast cell-driven diseases; the completion of the Phase 1 clinical trial for SEP-631 and planned presentation of topline data at AAAAI Annual Meeting in March 2026; the timing, progress and results of conducting our research and development programs, includingour plans to advance the TSHR program; the intended and potential benefits of the collaboration with Novo Nordisk, including our ability to jointly discover, develop and commercialize multiple potential oral small molecule therapies for obesity, type 2 diabetes, and other cardiometabolic diseases and the potential resulting milestones and royalties (if any); our ability to demonstrate, and the timing of, preclinical proof-of-concept in vivo and ex vivo for multiple programs; the potential of our proprietary Native Complex Platform ; the ability of preclinical observations to successfully translate into clinical outcomes; the size and growth potential of the markets for our current and future product candidates; our expectations regarding strategic plans for our business, product candidates, and technology; the scope of protection we are able to establish and maintain for intellectual property rights covering our Native Complex Platform and our product candidates; our ability to maintain existing collaborations and to identify and enter into future license agreements and collaborations; and the accuracy of our estimatesregarding expenses and capital requirements, including our expected cash runway at least into 2029. Such forward-looking statements reflect the current views of the Company and are subject to known and unknown risks and other factors, which are, in some cases, beyond the Company’s control. Risks that contribute to the uncertain nature of the forward- looking statements include those risks and uncertainties set forth in the section titled "Risk Factors" in our most recent Annual Report on Form 10-K for the year ended December 31, 2024, as well as any subsequent filings with the Securities and Exchange Commission. Certain information in this presentation (including market data and statistical information) and statements made orally during this presentation are the good faith estimates of management and have been obtained from various sources (including third-party sources such as independent industry publications, governmental publications, and reports by market research firms), and we do not guarantee the accuracy or completeness of such information. No representations or warranties (expressed or implied) are made about the accuracy of such forward-looking statements, and there can be no assurance as to the reliability or correctness of such projections and actual results may vary materially from those projected. The Company undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

Page 3

3© 2026 SEPTERNA 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 Validated targets + early clinical readouts + multi-billion $ market opportunities Well-capitalized Cash runway expected to support operating plans at least into 2029 GPCR: G protein-coupled receptor; Discovery Stage TSHR NAM: Potential disease -modifying treatment for Graves’ disease and TED; progressing multiple lead compounds toward development candidate selection Incretin Receptor Agonists: Potential multi-billion $ collaboration with Novo Nordisk for oral small molecules for metabolic diseases Lead Programs SEP-479 PTH1R Agonist: Potential first-in-class oral small molecule for hypoparathyroidism; Phase 1 clinical trial initiation anticipated in 1H 2026 SEP-631 MRGPRX2 NAM: Pipeline-in-a-product opportunity for mast cell -driven diseases (e.g., CSU); Phase 1 SAD/MAD results anticipated at AAAAI Annual Meeting in March 2026 NAM: negative allosteric modulator; TED: thyroid eye disease; CSU: chronic spontaneous urticaria; AAAAI: American Academy of Allergy, Asthma & Immunology

Page 4

4© 2026 SEPTERNA 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 approved products) target GPCRs ~75% of potential GPCR targets remain undrugged Our focus: Unlocking difficult-to-drug GPCRs with our Native Complex Platform

Page 5

5© 2026 SEPTERNA 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 LigandGPCR Native Complex Platform : Industrialized Workflows to Unlock Difficult-to-Drug GPCRs Native Complexes Retain GPCR natural structure, function, and dynamics High-Resolution GPCR Structures Technologies to Screen Billions of Compounds Discovery of new leads with relevant modes of action Novel binding pockets and new insights into GPCR modulation Structure-Based Drug Design & Optimization <1 year from initiation of med chem to activity in animal models for each program to date

Page 6

6© 2026 SEPTERNA Advancing a Deep Portfolio of Oral Small Molecule GPCR-Targeted Programs Wholly-Owned Programs Development Status Program / Target Mode of Action Therapeutic Area Indications / US Patient Population Discovery IND-enabling Phase 1 Phase 2 SEP-479 (PTH1R) Agonist Endocrinology Hypoparathyroidism: ~70k SEP-631 (MRGPRX2) Negative Allosteric Modulator Immunology and Inflammation CSU: ~1.5mm Other mast cell diseases TSHR Program Negative Allosteric Modulator Endocrinology Graves’ disease: ~2mm Thyroid eye disease: ~1mm Research Areas: Neurology, Women’s Health, Cardiovascular Disease and Respiratory Disease Partnered Programs Partner Metabolic Programs GLP-1R, GIPR, GCGR + Undisclosed Obesity and Other Cardiometabolic Diseases Undisclosed Undisclosed Anticipate Phase 1 topline data in late 2026 / early 2027 SAD/MAD presentation planned in March 2026 * Pending successful completion of regulatory submissions Phase 1 initiation* anticipated in 1H 2026

Page 7

Page 8

8 © 2026 SEPTERNA 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 Standard-of-care limitations • Calcium supplements (high doses several times per day) and Vitamin D do not fully resolve symptoms and lead to complications including calcifications and renal impairment • Approved injectable PTH therapy will require life -long daily injections Our Strategy: Functionally replace PTH with oral small molecule PTH1R agonist to normalize serum calcium PTH: Parathyroid Hormone PTH: Master Regulator of Blood Calcium

Page 9

9 © 2026 SEPTERNA Native Complex Platform Identified Portfolio of PTH1R Agonists with Potential to Address Significant Unmet Need in Hypoparathyroidism Multiple PTH1R agonists with distinct binding sites Native Complex Hit Identification Multiple PTH1R agonist series optimized in parallel Native Complex Structure-Based Design and Optimization Rapid Iterative Structure-Based Drug Discovery <1 year from initiation of medicinal chemistry to activity in an animal model PK: Pharmacokinetics PD: Pharmacodynamics PTH1R Multiple Compounds with Candidate Potential • Potent, selective, oral small molecules • Normalized serum calcium in preclinical animal models • Demonstrated comparable effects to PTH peptides in cell-based assays and animal models PTH SEP-479 • Next-generation oral small molecule PTH1R agonist candidate • Structurally unrelated to first clinical candidate (SEP-786) which was discontinued in Phase 1 due to off- target hyperbilirubinemia • Monkey PK/PD study demonstrated robust decreases in endogenous PTH and increases in serum calcium • Excellent pharmaceutical properties; projected to achieve full-day calcium control with QD dosing G protein

Page 10

10 © 2026 SEPTERNA 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: oral dosing QD: once daily dosing BID: twice daily dosing SEP-479: 28-day Oral QD Dosing Sustained Normalization of Serum Ca2+ Levels Sustained Normalization of Serum Phosphate Levels

Page 11

11 © 2026 SEPTERNA SEP-479: Preclinical Studies Demonstrated Favorable Oral Small Molecule Candidate Profile SEP-479: 7-day Healthy Cynomolgus Monkey Pharmacodynamic Study • Demonstrated robust dose -dependent decreases in endogenous PTH levels and increases in serum calcium • Lessons from PTH peptide therapies: doses that lead to ~0.5 -1 mg/dL calcium increases in healthy volunteers translated into rele vant therapeutic pharmacology in hypoparathyroidism patients SEP-479: Pharmacokinetics Studies (Mouse, Rat, Dog, Cyno) • Demonstrated high oral bioavailability and projected human half -life ~43-87 hours with potential to support QD human dosing Serum Ca2+ LevelsSerum PTH Levels

Page 12

12 © 2026 SEPTERNA SEP-479: On Track to Initiate Phase 1 in 1H 2026 Non-clinical safety studies have completed • 28-day GLP toxicology studies completed in rats, dogs, and cynomolgus monkeys • SEP-479 was generally well tolerated in all non -clinical safety studies • Dose-limiting effect in each species was on -target hypercalcemia, as expected for a PTH1R agonist • No hyperbilirubinemia or inhibition of UGT1A1 was observed in any of the non -clinical studies, even at supratherapeutic doses Drug product manufacturing for Phase 1 trial is on track Phase 1 healthy volunteer SAD / MAD trial planned for initiation in Australia in 1H 2026 • Goal: Evaluate the safety, tolerability, PK and PD of oral SEP-479 in healthy adult volunteers • PD activity to be assessed by decreases in endogenous PTH levels and increases in serum calcium • Anticipate topline data in late 2026 / early 2027

Page 13

Page 14

14 © 2026 SEPTERNA 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 cells are potentially drivers of several chronic allergic and inflammatory diseases • CSU, CIndU, prurigo nodularis, atopic dermatitis, allergic asthma, interstitial cystitis, migraine, and others CSU: Significant unmet need • ~1.5 million patients in US • Chronic symptoms include itchy, painful hives and angioedema that can impact quality of life • First-line treatment is high -dose anti-histamines with high unmet need for new second -line treatment options Our Strategy: MRGPRX2 NAM Inhibit mast cell activation by selectively blocking MRGPRX2 CIndU: Chronic Inducible Urticaria; NAM: Negative Allosteric Modulator

Page 15

15 © 2026 SEPTERNA IND-Enabling Safety Studies 28-day GLP toxicology studies in rats and dogs: generally well-tolerated Chronic Toxicology Studies 6-month rat and 9-month dog studies in progress; plan to complete prior to Phase 2 SEP-631: Clinical-Stage MRGPRX2 NAM with Potentially Differentiated Profile for Mast Cell-Driven Diseases Key Criteria for Advancement SEP-631 Complete High Potency High potency observed in multiple functional and binding assays Broad Inhibition Insurmountable inhibition of multiple endogenous agonists; long receptor residence time demonstrated in biophysical assays QD Oral PK Profile Excellent oral bioavailability in preclinical models; PK profile across species supports projected QD oral dosing in humans In vitro PD Potently inhibited primary human skin mast cell degranulation In vivo PD Potently inhibited skin extravasation in human MRGPRX2 knock-in mouse model Preclinical Profile: Non-Clinical Safety:

Page 16

16 © 2026 SEPTERNA 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 extravasation (MRGPRX2 inhibition) Knock-in Mouse mMRGPRB2 KO hMRGPRX2 KI • Primary human skin mast cells from skin donors stimulated with Substance P • SEP-631 potently inhibited tryptase release 0 3 0 2 4 6 8 SEP-631 (mg/kg, PO) Skin Evans Blue extravasation (fold over vehicle) p < 0.05 vehicle -12 -10 -8 -6 0 10 20 30 40 SEP-631 [log M] Tryptase release (% of total) SEP-631 Potently Inhibited Primary Human Skin Mast Cell Degranulation Intradermal skin challenge with Cortistatin-14 (MRGPRX2 agonist) KO: gene knockout KI: gene knock -in Complete Inhibition of Skin Extravasation with SEP-631

Page 17

17 © 2026 SEPTERNA SEP-631 Phase 1 Trial is on Track – Presentation of SAD / MAD Results Planned for AAAAI Annual Meeting in March 2026 Phase 1 Goal: Evaluate the safety, tolerability, PK and PD of oral SEP-631 in healthy adult volunteers Study design: • Randomized, placebo -controlled, single ascending dose (SAD) and multiple ascending dose (MAD) trial • Oral tablets; QD dosing in MAD x 10 days Intradermal skin challenge to assess early pharmacological activity in all MAD cohorts • Icatibant induces wheal response • Wheal response measured both prior to and following SEP -631 dosing Skin Challenge (Pre-dose) L H N P Skin Challenge Objective (Post -dose) L H N P SEP-631 dosing QD x 9 days L = low-dose icatibant; H = high-dose icatibant; N = negative control (saline); P = positive control (histamine) AAAAI: American Academy of Allergy, Asthma & Immunology

Page 18

Page 19

19 © 2026 SEPTERNA 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, thyroidectomy TED • Develops in ~50% of Graves’ disease patients • TEPEZZA® (anti -IGF-1R) decreases proptosis but requires multiple IV infusions; serious side effects (e.g., hearing loss) Challenge: Each Patient Has Unique Autoantibodies • High-affinity, frequently polyclonal, high titer Our Strategy: TSHR NAM as oral disease -modifying treatment for all Graves’ disease and TED patients

Page 20

20 © 2026 SEPTERNA 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 and Eye Manifestations 6 weeks 1 week Selective TSHR NAMs • Blocked activation of TSHR by patient - derived autoantibodies • Insurmountable NAM profiles in cell - based assays Preclinical Leads Inhibited Diverse Patient Autoantibodies • Fully inhibited several Graves’ patient polyclonal serum samples in primary orbital fibroblasts Reversed Graves’ Animal Disease Model Effects • Normalization of thyroid hormone T4 • Reduction in thyroid weight • Reversal of proptosis Vehicle Agonist mAb + Vehicle Agonist mAb + SP-1351 0 500 1000 1500Plasma T4 Levels (pg/dL) Vehicle Agonist mAb + Vehicle Agonist mAb + SP-1351 0.0 0.1 0.2 0.3Thyroid Weight (g) Lead optimization is ongoing towards selection of a development candidate

Page 21

Page 22

22 © 2026 SEPTERNA 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 GLP-1, GIP and glucagon receptors • Collaboration includes Septerna’s preclinical, selective, oral, small molecule GIP receptor agonists Potential multi-billion $ opportunity • $195M upfront payment received in July ‘25 • ~$500M in R&D, regulatory and commercial milestones for each program • Mid-to-high single-digit tiered royalties based on global product sales • Opt-in right for worldwide profit-share for one program Novo responsible for coverage of all collaboration R&D expenses Collaboration with Novo Nordisk for Oral Small Molecules for Metabolic Diseases

Page 23

Page 24

24 © 2026 SEPTERNA Proven Leaders in GPCR Drug Developmentand 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 Finer, MD, PhD, CEO • Jeff T ong, PhD, Third Rock Ventures • Alan Ezekowitz, MD, DPhil, Third Rock Ventures • Abe Bassan, Samsara BioCapital • Jake Simson, PhD, RA Capital • Bernard Coulie, MD, PhD, MBA, Independent Director • Shalini Sharp, MBA, Independent Director • Keith Gottesdiener, MD, Independent Director Academic Co-Founders • Robert J. Lefkowitz, MD, Duke University Medical Center • Arthur Christopoulos, PhD, Monash University • Patrick Sexton, PhD, DSc, Monash University Drug Discovery Advisory Board • Ruth Wexler, PhD, formerly with BMS • John Lowe, PhD, formerly with Pfizer • Craig Lindsley, PhD, Vanderbilt, formerly with Merck • T om Baillie, PhD, DSc, formerly with Merck • David Lacey, MD, formerly with Amgen Mark Wilson, JD CLO

Page 25

25 © 2026 SEPTERNA 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 cash runway expected to support operating plans at least into 2029 Wholly-Owned Programs Development Status Program / Target Mode of Action Discovery IND-enabling Phase 1 Phase 2 SEP-479 (PTH1R) Agonist SEP-631 (MRGPRX2) Negative Allosteric Modulator TSHR Program Negative Allosteric Modulator Partnered Programs Partner Metabolic Programs GLP-1R, GIPR, GCGR + Undisclosed Obesity and Other Cardiometabolic Diseases Undisclosed Undisclosed SAD/MAD presentation planned in March 2026 * Pending successful completion of regulatory submissions Anticipate Phase 1 topline data in late 2026 / early 2027 Phase 1 initiation* anticipated in 1H 2026

Page 26

Page 27

Page 28

28© 2026 SEPTERNA 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 Negative Allosteric Modulator GPCR A 4 8 12 16 20 B C D E F G # Structures 24 Native Complex High -Resolution GPCR Structures cryo-EM = cryogenic electron microscopy GPCR cryo-EM now achieving resolutions relevant for structure-based drug design Native Complex cryo-EM enables rapid and iterative lead optimization • Applies to a broad range of lead candidate modes of action (e.g., agonists, antagonists, allosteric modulators) • >150 high-resolution cryo-EM structures determined to date, fueling our drug discovery programs

Page 29

29 © 2026 SEPTERNA SEP-786: First Clinical PTH1R Agonist Discontinued in Phase 1 in February 2025 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 (normal AST, ALT , GGT), cholestasis, or hemolysis • Not predicted by preclinical studies including 28 -day GLP toxicology studies in rats and dogs Early signals of on-target pharmacology seen for SEP-786 prior to trial discontinuation • Observed initial increases in serum calcium and decreases in endogenous PTH (as anticipated for healthy subjects) • Observed human half -life of ~18 hours would have likely supported QD or BID oral dosing Investigation into the mechanism of unconjugated hyperbilirubinemia Post Clinical Discontinuation Findings: • SEP-786 is a potent UGT1A1 inhibitor* which is a known mechanism for increases in unconjugated bilirubin • In a cynomolgus monkey study with SEP -786 (conducted after clinical discontinuation), elevated unconjugated bilirubin was observed Bilirubin Bile Canaliculus Hepatocyte Hepatocyte Bilirubin Conjugated Bilirubin UGT1A1 OATP1B1 / OATP1B3 SEP-786 *Note: UGT1A1 is not routinely tested if glucuronidation is not the major drug metabolism pathway

Page 30

30 © 2026 SEPTERNA SEP-479: Preclinical Studies Demonstrated a Favorable Pharmacokinetic Profile 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 Predicted Human Half-life 9-27 hr Observed* Human Half-life 18 hr • SEP-479 demonstrated higher oral bioavailability across preclinical species and longer projected human half-life than SEP-786 • Human PK projections are anticipated to support QD oral dosing for SEP -479 *Approximate SEP-786 half-life from Phase 1 clinical trial

Slides