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Nasdaq: SEPN Pioneering a New Era of GPCR Drug Discovery January 2025 J.P . Morgan Healthcare Conference 2025
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2© 2025 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 milestones and objectives of management are forward-looking statements. Such forward-looking statements include, but are not limited to, statements regarding: the continued development and advancement of our oral small molecule GPCR-targeted programs; the initiation, timing, progress, and results of conducting our research and development programs and our current and future preclinical studies and anticipated clinical trials, and the release of data related thereto; 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 accuracy of our estimates regarding expenses and capital requirements, including our expected cash runway; the size and growth potential of the markets for our current and future product candidates and our ability to serve those markets; and our expectations regarding the implementation of our business model, and strategic plans for our business, product candidates, and technology. 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 Quarterly Report on Form 10-Q for the quarter ended September 30, 2024, filed with the Securities and Exchange Commission (the “SEC”) and in our subsequent filings with the SEC. 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.
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3© 2025 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 with a planned operating runway into 2H 2027 GPCR = G protein-coupled receptor; Discovery Stage TSHR NAM: Potential first disease-modifying treatment for Graves’ disease and TED Incretin Receptor Agonists: Opportunities for single- and multi-incretin receptor agonists for metabolic diseases (e.g., obesity and T2D) Lead Candidates SEP-786 PTH1R Agonist: Potential first-in-class oral small molecule for hypoparathyroidism; Phase 1 underway with SAD/MAD data expected in mid-2025 SEP-631 MRGPRX2 NAM: Pipeline-in-a-product opportunity for mast cell diseases (e.g., CSU); Phase 1 initiation expected in 2025 NAM = negative allosteric modulator; TED = thyroid eye disease; CSU = chronic spontaneous urticaria; T2D = Type 2 diabetes
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4© 2025 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
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5© 2025 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
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6© 2025 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)
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7© 2025 SEPTERNA Advancing a Deep Portfolio of Oral Small Molecule GPCR-Targeted Programs Programs Development Status Program / Target Mode of Action Therapeutic Area Indications / US Patient Population Discovery IND-enabling Phase 1 Phase 2 Phase 3 SEP-786 (PTH1R) Agonist Endocrinology Hypoparathyroidism: ~70k SEP-631 (MRGPRX2) Negative Allosteric Modulator Immunology and Inflammation CSU: ~1.5mm Other mast cell diseases TSHR Negative Allosteric Modulator Endocrinology Graves’ disease: ~2mm Thyroid eye disease: ~1mm GLP-1R, GIPR, GCGR Single- and Multi-Agonists Metabolic Diseases Obesity and T2D: ~800mm (worldwide) Other metabolic diseases Other Therapeutic Areas of Interest / Focus: Neurology, Women’s Health, Cardiovascular Disease and Respiratory Disease Note: Vertex acquired an undisclosed discovery-stage program in 2023 for $47.5M upfront
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© 2025 SEPTERNA SEP-786: Oral Small Molecule PTH1R Agonist Targeting PTH1R for Hypoparathyroidism
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9 © 2025 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 Inadequate standard -of-care • 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 Injectable PTH therapies approved and in development • Will require life-long injections Our Strategy: Develop oral PTH1R agonist Functionally replace PTH with oral small molecule to normalize serum calcium PTH = Parathyroid Hormone PTH: Master Regulator of Blood Calcium
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10 © 2025 SEPTERNA SEP-786: Product of Our Native Complex Platform Drug Discovery • Potent, selective oral small molecule • Normalized serum calcium in preclinical model • PK/PD model projects full-day calcium control with QD or BID dosing • Currently in Phase 1 clinical trial PTH1R SEP-786 Multiple PTH1R agonists with distinct binding sites Native Complex Hit Identification Native Complex Lead Optimization Led to SEP-786Multiple PTH1R agonist series optimized in parallel Native Complex Structure-Based Design Rapid Iterative Structure-Based Drug Discovery <1 year from initiation of medicinal chemistry to activity in an animal model QD = once-daily dosing BID = twice-daily dosing PK = pharmacokinetics PD = pharmacodynamics
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11 © 2025 SEPTERNA SEP-786 Demonstrated Potent, Selective Activation of PTH1R and Dose-dependent Serum Calcium Increases 28-day dosing Sustained Ca2+ control Single-dose Matches efficacy of peptide Surgery to remove parathyroid glands Rat Decreased serum calcium (hypocalcemia) PTH1R agonist (SEP-786) Normalize serum calcium Rat surgical model of hypoparathyroidism 6h 9h18h24h 6h 9h18h24h 6h 9h18h24h 6h 9h18h24h 1 2 3 4Serum Ca2+ level (mmol/L) Day 1 Day 10 Day 19 Day 28 Vehicle (PO) SEP-786 (PO, 3 mg/kg BID) Normal serum Ca2+ range 6h 9h18h24h 6h 9h18h24h 6h 9h18h24h 6h 9h18h24h 1 2 3 4Serum Ca2+ level (mmol/L) Day 1 Day 10 Day 19 Day 28 Vehicle (PO) SEP-786 (PO, 3 mg/kg BID) Normal serum Ca2+ range 0 6 12 18 24 1 2 3 4 Time (hr) Serum Ca2+ level (mmol/L) SEP-786 (PO, 3 mg/kg) SEP-786 (PO, 10 mg/kg) SEP-786 (PO, 30 mg/kg) LA-PTH (SC, 2 nmol/kg) Vehicle (PO) Normal serum Ca2+ range 0 6 12 18 24 1 2 3 4 Time (hr) Serum Ca2+ level (mmol/L) SEP-786 (PO, 3 mg/kg) SEP-786 (PO, 10 mg/kg) SEP-786 (PO, 30 mg/kg) LA-PTH (SC, 2 nmol/kg) Vehicle (PO) Normal serum Ca2+ range 0 6 12 18 24 1 2 3 4 Time (hr) Serum Ca2+ level (mmol/L) SEP-786 (PO, 3 mg/kg) SEP-786 (PO, 10 mg/kg) SEP-786 (PO, 30 mg/kg) LA-PTH (SC, 2 nmol/kg) Vehicle (PO) Normal serum Ca2+ range PO = oral dosing SC = subcutaneous dosing
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12 © 2025 SEPTERNA SEP-786: Phase 1 Trial Underway, Data Expected Mid-2025 Preclinical data supports clinical development • PK studies in mice, rats, dogs, and monkeys support predicted human PK for QD or BID dosing • 28-day GLP toxicology studies in rats and dogs: generally well -tolerated • Effects of exaggerated on -target pharmacology seen at high doses Phase 1 clinical trial underway – data anticipated mid-2025 • Single-ascending dose (SAD) & multiple -ascending dose (MAD) trial in healthy volunteers • MAD portion to assess both QD and BID dosing • Primary endpoints: safety and tolerability • Secondary endpoints: PK, serum calcium, other biomarkers
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© 2025 SEPTERNA SEP-631: Oral Small Molecule MRGPRX2 NAM Targeting MRGPRX2 for Mast Cell Disorders, Including CSU
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14 © 2025 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 Cell-Driven Diseases • CSU, atopic dermatitis, allergic asthma, and others CSU: Significant Unmet Need • ~1.5 million patients in US • Itchy, painful hives and angioedema • Chronic symptoms can impact quality of life • First-line treatment: antihistamines; 37% refractory • Second-line treatment: anti-IgE (Xolair); 64% refractory Our Strategy: MRGPRX2 NAM Inhibit mast cell activation by selectively blocking MRGPRX2 NAM= Negative Allosteric Modulator
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15 © 2025 SEPTERNA SEP-631: Oral Small Molecule MRGPRX2 NAM Designed to Stop MRGPRX2-Mediated Mast Cell Degranulation SEP-631 Potently Inhibited Skin Extravasation in MRGPRX2 Knock-in 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 SEP-631: Selective MRGPRX2 NAM • Potent oral small molecule • Blocked activation of all endogenous MRGPRX2 activators • Showed insurmountable NAM profile with long-lasting inhibition Effective in Preclinical Models • Prevented skin extravasation in human MRGPRX2 knock-in mouse • Potently inhibited degranulation of primary human mast cells • Demonstrated good PK properties and has been generally well tolerated in preclinical safety models to date 0 3 0 2 4 6 8 SEP-631 (mg/kg, PO) Skin Evans Blue extravasation (fold over vehicle) p < 0.05 vehicle Intradermal skin challenge with Cortistatin-14 (MRGPRX2 agonist)
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16 © 2025 SEPTERNA SEP-631: MRGPRX2 NAM with Potentially Differentiated Profile Key Criteria SEP-631 High Potency Demonstrated in multiple functional and binding assays Broad Inhibition Long residence time and insurmountable inhibition of multiple endogenous agonists Good Oral PK Excellent oral bioavailability; PK profile across species supports QD oral dosing projection in humans In vitro PD Activity in primary human skin mast cells In vivo PD Activity in hMRGPRX2 knock-in mice Favorable in vivo safety profile 14-day non-GLP studies in rat and dog showed a generally favorable tolerability profile IND-enabling studies ongoing to support advancement into Phase 1 clinical trial in 2025
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© 2025 SEPTERNA TSHR NAM Program Targeting TSHR for Graves’ Disease and TED
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18 © 2025 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) Drug Discovery Challenge: Each Patient Has Unique Autoantibodies • High-affinity, frequently polyclonal, high titer Our Strategy: TSHR NAM Oral disease-modifying treatment for all Graves’ disease and TED patients NAM= Negative Allosteric Modulator
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19 © 2025 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 • Demonstrate insurmountable profiles 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 mAb = monoclonal antibody 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)
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© 2025 SEPTERNA Oral Small Molecule Incretin Receptor Agonist Programs Single- and Multi-GLP-1R, GIPR, and GCGR Agonists for Metabolic Disorders, Including Obesity and Type 2 Diabetes
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21 © 2025 SEPTERNA Next-Generation Oral Incretin Receptor Agonists Incretin peptide therapeutics have been transformative treatments for obesity and diabetes • Marketed GLP-1 and GLP-1/GIP products generated ~$36B in global sales in 2023 • Limitations: tolerability, injection administration, prolonged titration schemes Our Strategy: Next -generation incretin receptor agonists Oral small molecule single- and multi-incretin receptor agonists that can be used as single medicines or in combination Septerna Binding Site Danuglipron & Orforglipron Sites vs. Approximate % sequence similarity across GLP-1R, GIPR, CGCR 80 - 90% 40 - 60% Novel binding pocket identified with potential to develop both single- and multi-incretin receptor agonists • Pocket has higher sequence similarity across GLP -1R, GIPR, GCGR than known binding sites occupied by clinical -stage GLP-1R small molecule agonists
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22 © 2025 SEPTERNA Discovery of Oral Small Molecule Single - and Multi-Incretin Receptor Agonists Example: Selective mono-GIPR agonists demonstrated weight loss both alone and with additive activity in combination with a GLP-1 peptide • Diet-induced obese (DIO) mouse model +/- semaglutide 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 60 70 80 90 100 110 Days Body Weight (%) Semaglutide (SC, 10 nmol/kg) Vehicle (PO) SP-2991 (PO, 30 mg/kg) Vehicle (SC) SP-2991 (PO, 30 mg/kg) Semaglutide (SC, 10 nmol/kg) Tirzepatide (SC, 10 nmol/kg) Vehicle (PO) Vehicle (PO) Vehicle (SC)~7% ~24% ~33% p < 0.05 p < 0.005 QD dosing Identified Multiple Incretin Receptor Agonist Chemical Series • Activity spans combinations of activities across GLP-1R, GIPR, and GCGR Optimizing Both Single- and Multi- Incretin Agonist Leads Focused on: • Mono-GIPR agonists • Dual-GIPR / GCGR agonists • Triple-GLP-1R / GIPR / GCGR agonists
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© 2025 SEPTERNA Building a World-Class GPCR-Focused Biotechnology Company
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24 © 2025 SEPTERNA Proven Leaders in GPCR Drug Development and Company Building Senior Leadership Jeff Finer, MD PhD CEO Liz Bhatt, MS MBA 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 Tong, PhD, Third Rock Ventures • Alan Ezekowitz, MD, DPhil, Third Rock Ventures • Abe Bassan, Samsara BioCapital • Jake Simson, PhD, RA Capital • Bernard Coulie, MD, PhD, Independent Director • Shalini Sharp, MBA, 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 • David Lacey, MD, formerly with Amgen • John Lowe, PhD, formerly with Pfizer • Craig Lindsley, PhD, Vanderbilt, formerly with Merck
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25 © 2025 SEPTERNA Septerna: Pioneering a New Era of GPCR Drug Discovery Program / Target Mode of Action Therapeutic Area Indications Discovery IND- enabling Phase 1 Phase 2 Phase 3 SEP-786 (PTH1R) Agonist Endocrinology Hypoparathyroidism SEP-631 (MRGPRX2) Negative Allosteric Modulator Immunology and Inflammation CSU and other mast cells diseases TSHR Negative Allosteric Modulator Endocrinology Graves’ disease and TED GLP-1R, GIPR, GCGR Single- and Multi- Agonists Metabolic Diseases Obesity and T2D Wholly-owned pipeline of programs, each with a multi-billion $ market opportunity SAD/MAD data mid-2025 Phase 1 initiation in 2025 • Clinical-stage lead program with data expected mid-2025 • Multi-product pipeline focused on large commercial markets • Native Complex Platform to drive rapid pipeline expansion • Well capitalized with operating runway into 2H 2027
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© 2025 SEPTERNA Pioneering a New Era of GPCR Drug Discovery