EX-99.1 2 d946079dex991.htm EX-99.1

Nasdaq: SEPN Pioneering a New Era of GPCR Drug Discovery September 2025 Corporate Presentation Exhibit 99.1

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 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 preclinical activities 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 CSU and other mast cell-driven diseases; the role of MRGPRX2 in mast cell-driven diseases; the ability to enroll patients and complete the Phase 1 clinical trial for SEP-631 according to estimated timelines, including the anticipated timing of initial clinical data in the first half of 2026; results of conducting our research and development programs, including our plans to advance the TSHR NAM 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 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 of 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 estimates regarding 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.

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 Updated cash runway expected to support operating plans at least into 2029* GPCR = G protein-coupled receptor; Discovery Stage TSHR NAM: Potential first 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; preclinical studies underway; Phase 1 clinical trial initiation anticipated in 1H 2026 SEP-631 MRGPRX2 NAM: Pipeline-in-a-product opportunity for mast cell diseases (e.g., CSU); Phase 1 trial in healthy volunteers initiated in Aug 2025 with initial SAD/MAD data anticipated in 1H 2026 NAM = negative allosteric modulator; TED = thyroid eye disease; CSU = chronic spontaneous urticaria *Following receipt of $195.0 million upfront payment from Novo Nordisk in July 2025 and a $12.5 million milestone payment from Vertex in August 2025

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™

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 Ligand GPCR 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

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) >100 high-resolution cryo-EM structures determined to date, fueling our drug discovery 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: ~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 a Metabolic Programs GLP-1R, GIPR, GCGR + Undisclosed Obesity and Other Cardiometabolic Diseases Undisclosed Undisclosed

PTH1R Agonist Program Oral Small Molecule Targeting PTH1R for Hypoparathyroidism

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: Functionally replace PTH with oral small molecule PTH1R agonist to normalize serum calcium PTH = Parathyroid Hormone PTH: Master Regulator of Blood Calcium

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-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 Normalize serum calcium in preclinical animal models PK/PD projects potential for full-day calcium control in hypoparathyroidism patients Generally well tolerated in preclinical studies SEP-786: Discontinued First Candidate Phase 1 discontinued in Feb ’25 due to unexpected events Unconjugated hyperbilirubinemia determined to be due to off-target effect Early signals of on-target clinical pharmacology prior to trial discontinuation PK profile appeared to support QD or BID dosing SEP-479: Next-Generation Candidate Development candidate selected Structurally unrelated to SEP-786 and does not share the same off-target effect in preclinical studies Activity observed in animal models at significantly lower doses than SEP-786 Longer projected human half-life than SEP-786 supporting potential for QD dosing PTH

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 (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 MRP2 SEP-786 *Note: UGT1A1 is not routinely tested if glucuronidation is not the major drug metabolism pathway

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 Note: SEP-479 activity at 0.15 mg/kg QD was comparable to prior SEP-786 activity in this model at 3 mg/kg BID

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 Predicted Human Half-life 9-27 hr Observed Human Half-life 18 hr Pharmacokinetics SEP-479 demonstrated high oral bioavailability across preclinical species and human PK projections are anticipated to support QD oral dosing Pharmacodynamics 7-day PK/PD studies in healthy cynomolgus monkeys Demonstrated robust dose-dependent increases in serum calcium and decreases in endogenous PTH levels Lessons from PTH peptide therapies: doses that lead to ~1 mg/dL calcium increases in healthy volunteers translated into relevant therapeutic pharmacology in hypoparathyroidism patients 7-day Cyno PD Study Serum Ca2+ Levels 7-day Cyno PD Study Serum PTH Levels

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 with supratherapeutic doses 28-day GLP toxicology studies completed in rats and dogs, and SEP-479 was generally well tolerated 28-day GLP toxicology study in cynomolgus monkeys to be completed prior to Phase 1 initiation (added as an additional safety species based on SEP-786 experience) SEP-479 Manufacturing Drug substance and drug product manufacturing for Phase 1 supply is underway Plans to initiate SEP-479 Phase 1 clinical trial in 1H 2026 pending successful completion of IND-enabling studies, drug product manufacturing, and regulatory submissions

SEP-631: Oral Small Molecule MRGPRX2 NAM Targeting MRGPRX2 for Mast Cell Disorders, Including CSU

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

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 relevant MRGPRX2 agonists SEP-631 demonstrated strong suppression of maximal agonist effects in vitro Matrix of concentrations of SEP-631 vs. cortistatin-14 Strong suppression of maximal agonist effects is consistent with an insurmountable NAM profile

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 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

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 Excellent oral bioavailability in preclinical models; 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 28-day GLP toxicology studies in rat and dog: generally well-tolerated IND-enabling studies Completed and fully supported advancing into Phase 1

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 (MAD) trial Oral tablets, QD dosing in MAD Estimated ~150 healthy adult volunteers Intradermal skin challenge to assess early pharmacological activity Icatibant induces wheal response Measure inhibition of wheal response 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; P = positive control

TSHR NAM Program Oral Small Molecule Targeting TSHR for Graves’ Disease and 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 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

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 serum samples isolated from TED surgery patients TSHR NAM fully inhibited activity of 10 out of 10 Graves’ disease patient-derived polyclonal serum samples Suggests broad inhibitory activity against diverse range of polyclonal patient autoantibodies mAb = monoclonal antibody

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 Novel Mouse Model of Graves’ Disease Treatment of mice with a patient-derived autoantibody for 6 weeks induced signs similar to Graves’ disease and TED TSHR NAM Reversed Graves’ Animal Model Effects Normalization of thyroid hormone T4 Reduction in thyroid weight Reversal of proptosis

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

Building a World-Class GPCR-Focused Biotechnology Company

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 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, MBA, 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 John Lowe, PhD, formerly with Pfizer Craig Lindsley, PhD, Vanderbilt, formerly with Merck Tom Baillie, PhD, DSc, formerly with Merck David Lacey, MD, formerly with Amgen

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 cash runway expected to support operating plans at least into 20291 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 Phase 1 initiation2 anticipated in 1H 2026 SAD/MAD data anticipated in 1H 2026 Following receipt of $195.0 million upfront payment from Novo Nordisk in July 2025 and a $12.5 million milestone payment from Vertex in August 2025 Pending successful completion of preclinical activities and regulatory submissions

Pioneering a New Era of GPCR Drug Discovery