Septerna selects SEP-204; trial expected in Q1 2027
Septerna expects its cash runway to support operating plans at least into 2029; SEP-631’s Phase 1 data included an approximately 24-hour half-life.
Sentiment and the balance of points
Rhea-AI Sentiment reads the wording of the document, how positive or negative its language is on a 1 to 5 scale. The balance of points shown with the takes weighs what the document actually discloses, so the two can disagree, for example when a trial that missed its main goal is described in upbeat language.
Rhea-AI Filing Summary
Septerna, Inc. selected SEP-204, an oral small-molecule thyroid-stimulating hormone receptor (TSHR) negative allosteric modulator, as a potential first-in-class development candidate for Graves’ disease and thyroid eye disease. Preclinical studies reported inhibition of TSHR activation in Graves’ disease models; a Phase 1 study in healthy volunteers is anticipated to begin in the first quarter of 2027.
The corporate presentation reports SEP-631 Phase 1 results, including an approximately 24-hour elimination half-life and inhibition of icatibant-induced skin wheal formation. No severe or serious events were observed, and adverse-event rates were comparable with placebo. SEP-479 Phase 1 dosing is ongoing, with SAD/MAD results anticipated in Q1 2027.
Septerna said its cash runway is expected to support operating plans at least into 2029. Its Novo collaboration included a $195 million upfront payment received in July 2025 and approximately $500 million in research, regulatory and commercial milestones for each program, plus mid-to-high single-digit tiered royalties based on global product sales.
8-K Event Classification
Key Figures
Key Terms
negative allosteric modulator (NAM) technical
pharmacokinetic properties technical
single ascending dose (SAD) and multiple ascending dose (MAD) technical
receptor occupancy technical
FAQ
AI-generated questions and answers. How Rhea-AI works. Not financial advice.
What is SEPN’s SEP-204 program, and when is its Phase 1 trial expected?
What did SEPN report from SEP-631’s Phase 1 study?
What are the disclosed financial terms of SEPN’s Novo collaboration?
AI-generated analysis. How Rhea-AI works. Not financial advice.
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported):
(Exact name of Registrant as Specified in Its Charter)
| (State or Other Jurisdiction of Incorporation) |
(Commission File Number) |
(IRS Employer Identification No.) |
| (Address of Principal Executive Offices) | (Zip Code) |
Registrant’s Telephone Number, Including Area Code:
Not Applicable
(Former Name or Former Address, if Changed Since Last Report)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
| Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425) |
| Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12) |
| Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b)) |
| Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c)) |
Securities registered pursuant to Section 12(b) of the Act:
| Title of each class |
Trading Symbol(s) |
Name of each exchange | ||
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§ 230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§ 240.12b-2 of this chapter).
Emerging growth company
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act.
| Item 7.01 | Regulation FD Disclosure. |
On November 4, 2026, Septerna, Inc., or Septerna, issued a press release titled “Septerna Announces Selection of SEP-204 as Development Candidate for Graves’ Disease and TED and Reports Preclinical Data at the 2026 American Thyroid Association Annual Meeting.” A copy of the press release is furnished as Exhibit 99.1 to this Current Report on Form 8-K and is incorporated herein by reference.
On November 4, 2026, Septerna also updated its corporate presentation for use in meetings with investors, analysts and others. A copy of the updated corporate presentation is furnished as Exhibit 99.2 to this Current Report on Form 8-K, which is incorporated herein by reference.
The information in Item 7.01 of this Current Report on Form 8-K, including the accompanying Exhibit 99.1 and Exhibit 99.2, is intended to be furnished and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, regardless of the general incorporation language of such filing, except as shall be expressly set forth by specific reference in such filing.
| Item 9.01. | Financial Statements and Exhibits. |
(d) Exhibits
| 99.1 | Press Release issued by Septerna, Inc. on November 4, 2026, furnished herewith. |
| 99.2 | Corporate Presentation of Septerna, Inc., dated November 2026, furnished herewith. |
| 104 | Cover Page Interactive Data File (embedded within the Inline XBRL document). |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| Septerna, Inc. | ||||||
| Date: November 4, 2026 | By: | /s/ Jeffrey Finer, M.D., Ph.D. | ||||
| Jeffrey Finer, M.D., Ph.D. Chief Executive Officer | ||||||
Exhibit 99.1
Septerna Announces Selection of SEP-204 as Development Candidate for Graves’ Disease and TED and Reports Preclinical Data at the 2026 American Thyroid Association Annual Meeting
Potent, selective TSHR NAM with pre-clinical activity demonstrated across biochemical, thyroid and ocular endpoints
Favorable PK profile anticipated to support once-daily oral dosing in humans
Phase 1 clinical trial initiation planned for the first quarter of 2027
SOUTH SAN FRANCISCO, Calif. – November 4, 2026 – Septerna, Inc. (Nasdaq: SEPN), a clinical-stage biotechnology company pioneering a new era of G protein-coupled receptor (GPCR) drug discovery, today announced the selection of SEP-204 as its potential first-in-class development candidate for the treatment of Graves’ disease and thyroid eye disease (TED) and reported initial preclinical data ahead of a poster presentation at the 2026 American Thyroid Association (ATA) Annual Meeting on November 5.
SEP-204 is a potent and selective oral small molecule thyroid-stimulating hormone receptor (TSHR) negative allosteric modulator (NAM). SEP-204 inhibited TSHR activation in Graves’ disease animal models and has pharmacokinetic properties to support once daily dosing. A Phase 1 trial in healthy volunteers is anticipated to initiate in the first quarter of 2027.
“Based on the pre-clinical data we have generated to date, we believe SEP-204 has the potential to change the treatment paradigm for Graves’ disease and TED, two serious autoimmune endocrine diseases that can profoundly affect patients’ health and quality of life,” said Rajiv Patni, chief medical officer of Septerna. “We look forward to working closely with disease experts and the patient community to advance SEP-204 into clinical development and build upon these promising preclinical findings with clinical results.”
Preclinical studies of SEP-204 demonstrated the following key findings:
| • | Potent TSHR inhibition with desirable drug-like properties and a high level of selectivity over the closely related follicle-stimulating hormone receptor (FSHR) and luteinizing hormone receptor (LHR). |
| • | Inhibition of thyroid-stimulating antibody (TSAb) activation of TSHR in human thyrocyte cell assays. |
| • | In Graves’ disease animal models, findings included restoration of normal thyroid hormone T4 levels and reductions in thyroid enlargement and orbital proptosis. |
| • | Dose-dependent increases in TSH levels followed by decreases in thyroid hormone levels were observed across preclinical species. |
| • | Generally well tolerated in 28-day GLP toxicology studies in rats and dogs. |
| • | High oral bioavailability and low clearance across preclinical species, with a projected human half-life of approximately 20-40 hours, which is anticipated to support once-daily oral dosing in humans. |
About SEP-204, Graves’ Disease and Thyroid Eye Disease
SEP-204 is an investigational oral small molecule thyroid-stimulating hormone receptor (TSHR) negative allosteric modulator (NAM) being developed as a potential disease-modifying treatment for Graves’ disease and thyroid eye disease (TED). It is designed to block the overactivation of TSHR caused by patients’ autoantibodies in thyroid cells and orbital fibroblasts and has the potential to address both conditions. Graves’ disease is an autoimmune condition in which antibodies activate TSHR, stimulating excess thyroid hormone production and causing hyperthyroidism. Some patients also develop TED, a serious, potentially vision-threatening autoimmune condition affecting tissues behind the eyes that can cause eye bulging, swelling, pain and blurred or double vision. Current standard-of-care treatments do not address the shared underlying cause of both Graves’ disease and TED.
About Septerna
Septerna, Inc. is a clinical-stage biotechnology company with a world-class team of GPCR experts and drug developers advancing cutting-edge science to unlock the full potential of GPCR therapies for patients with significant unmet needs. The company’s proprietary Native Complex Platform® is designed to enable new approaches to GPCR drug discovery and has led to the development of a diverse pipeline of novel oral small molecule drug candidates. Septerna is advancing programs in endocrinology, immunology and inflammation, metabolic diseases and additional therapeutic areas, both independently and with partners. For more information, please visit www.septerna.com.
Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, including, without limitation, implied and express statements about Septerna’s beliefs and expectations regarding: the potential translation of preclinical findings to clinical outcomes in patients; the potential of SEP-204 to be a first-in-class, disease-modifying treatment for Graves’ disease and TED; advancing SEP-204 into a Phase 1 clinical study and the timing thereof; SEP-204’s potential for once daily dosing; the potential of its proprietary Native Complex Platform®; and the scope of protection it is able to establish and maintain for intellectual property rights covering its Native Complex Platform® and its product candidates; among others. The words “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “might,” “objective,” “ongoing,” “plan,” “predict,” “project,” “potential,” “should,” or “would,” or the negative of these terms, or other comparable terminology are intended to identify forward-looking statements, although not all forward looking statements contain these identifying words.
Any forward-looking statements in this press release are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks associated with: SEP-204 successfully entering and advancing through clinical trials including uncertainties related to opening investigational new drug applications and obtaining other regulatory approvals; risks related to clinical development outcomes including unexpected safety or efficacy findings; the results of preclinical studies not being predictive of future clinical outcomes; risks related to the timing of initiating clinical studies; and the scope of protection Septerna is able to establish and maintain for intellectual property rights covering its Native Complex Platform® and its product candidates; among others. These and other risks and uncertainties are described in greater detail in the section entitled “Risk Factors” in Septerna’s Quarterly Report on Form 10-Q for the three months ended June 30, 2026, as well as any subsequent filings with the Securities and Exchange Commission. In addition, any forward-looking statements represent Septerna’s views only as of today and should not be relied upon as representing its views as of any subsequent date. Septerna explicitly disclaims any obligation to update any forward-looking statements subject to any obligations under applicable law. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements.
Investor Contact:
Renee Leck, THRUST
renee@thrustsc.com
Media Contact:
Carly Scaduto, THRUST
carly@thrustsc.com
Exhibit 99.2 Pioneering a New Era of GPCR Drug Discovery Corporate Presentation November 2026 Nasdaq: SEPN © 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, express or implied statements regarding: the continued advancement of SEP-479 in clinical development, including the anticipated timing for the availability of data; our plans to advance SEP-204 into a Phase 1 clinical study and timing thereof; SEP-204’s potential as an oral disease- modifying treatment for Graves’s disease and thyroid eye disease; the continued advancement of SEP-631, including our plan to evaluate strategies for capital- efficient, signal-finding clinical studies across multiple indications; the role of MRGPRX2 in mast cell-driven diseases; the ability of preclinical or Phase 1 observations to successfully translate into positive clinical outcomes; the timing, progress and results of conducting our research and development programs; the intended and potential benefits of the collaboration with Novo, 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 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 estimates regarding expenses and capital requirements, including our expected cash runway, among others. Such forward-looking statements reflect Septerna’s current views 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 risks related to biopharmaceutical development and conducting preclinical studies and clinical trials, along with those risks and uncertainties set forth in the section titled Risk Factors in our most recent Quarterly Report on Form 10-Q for the three months ended June 30, 2026, 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. © 2026 SEPTERNA 2
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-modifying ® Native Complex Platform designed to unlock the treatment for Graves’ disease and TED; anticipate initiating Phase 1 in healthy volunteers in Q1 2027 full potential of GPCR therapies • Iterative structure-based drug design to rapidly optimize SEP-631 MRGPRX2 NAM: Pipeline-in-a-product and validate programs in animal models opportunity for mast cell-driven diseases; Phase 1 demonstrated robust PD with QD dosing; evaluating Portfolio strategy to drive value creation multi-indication clinical signal-finding strategy • Validated targets + early clinical readouts + multi-billion $ market opportunities Discovery Stage Well-capitalized PTH1R Agonists: Potential oral small molecule anabolic treatment for osteoporosis • Cash runway expected to support operating plans at least into 2029 Incretin Receptor Agonists: Potential multi-billion $ collaboration with Novo for oral small molecules for metabolic diseases © 2026 SEPTERNA GPCR: G protein-coupled receptor; 3 NAM: negative allosteric modulator; TED: thyroid eye disease
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 small subfamilies of GPCRs ~75% of potential GPCR targets remain undrugged Our focus: Unlocking difficult-to-drug GPCRs ® with our Native Complex Platform © 2026 SEPTERNA 4
® 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 Platform : Industrialized Workflows to Unlock Difficult-to-Drug GPCRs Native High-Resolution Technologies to Screen Structure-Based Drug Complexes GPCR Structures Billions of Compounds Design & Optimization Ligand GPCR Lipid Bilayer G protein Retain GPCR natural structure, Novel binding pockets and new Discovery of new leads with <1 year from initiation of med function, and dynamics insights into GPCR modulation relevant modes of action chem to activity in animal models for each program to date © 2026 SEPTERNA 5
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 Agonist Endocrinology Anticipate Phase 1 SEP-204 (TSHR) Graves’ disease & initiation in Q1 2027 Negative Allosteric Modulator Thyroid eye disease Immunology and Inflammation SEP-631 (MRGPRX2) Mast cell-driven diseases Negative Allosteric Modulator Endocrinology PTH1R Program Osteoporosis Agonist Research Areas: Neurology, Women’s Health, Cardiovascular Disease and Respiratory Disease Partnered Programs Partner Metabolic Programs Obesity and Other Cardiometabolic Diseases GLP-1R, GIPR, GCGR* © 2026 SEPTERNA 6 * Partnership also includes two undisclosed targets
SEP-479: Oral Small Molecule PTH1R Agonist Targeting PTH1R for Hypoparathyroidism © 2026 SEPTERNA
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 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 © 2026 SEPTERNA 8 PTH: Parathyroid Hormone
® 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 quality molecules Potent oral small molecule PTH1R agonist Demonstrated comparable effects to PTH peptides in cell- based assays and in vivo models PTH Normalized serum calcium in preclinical rat surgical model of hypoparathyroidism Rapid Iterative Structure-Based PTH1R Monkey PK/PD study demonstrated robust decreases in Drug Discovery endogenous PTH and increases in serum calcium Excellent pharmaceutical properties; projected to achieve full-day HypoPT control with QD dosing <1 year from initiation of medicinal chemistry to Generally well tolerated in GLP toxicology studies G protein activity in an animal model Phase 1 in healthy volunteers is in progress © 2026 SEPTERNA 9
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 1.5 15 6 1.0 1.0 10 4 0.5 0.5 5 2 0 0.0 0.0 0 • Suppressed sclerostin and upregulated osteocalcin • Increased RANKL and decreased osteoprotegerin expression, suggesting promotion of osteoprogenitor transcription, suggesting promotion of osteoclast differentiation and enhancement of bone formation differentiation and acceleration of bone resorption © 2026 SEPTERNA 10 Methods: UMR-106 cells were treated with PTH (1-34) or SEP-479 for 5 hours; gene expression analyzed by quantitative RT-PCR; SEP-479: 10 nM; PTH (1-34): 0.1 nM Vehicle PTH (1-34) SEP-479 Vehicle PTH (1-34) SEP-479 Vehicle PTH (1-34) SEP-479 Vehicle PTH (1-34) SEP-479 Sost rel. expression Bglap rel. expression Tnfsf11 rel. expression Tnfrsf11b rel. expression
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 serum calcium (hypocalcemia) Oral small molecule PTH1R agonist Normalize serum calcium © 2026 SEPTERNA 11 PO: oral dosing QD: once daily dosing
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) • Decreased urinary calcium concentration and and modestly changed P1NP (serum bone anabolic marker) increased active Vitamin D production Urinary Calcium Active Vitamin D Bone Mineral Density Serum Bone Biomarkers Femur Serum P1NP Tibia Serum CTX 200 200 200 150 200 150 150 150 150 150 100 100 100 100 100 100 50 50 50 50 50 50 0 0 0 0 0 0 Vehicle 0.15 0.2 Vehicle 0.15 0.2 Vehicle 0.15 0.2 Vehicle 0.15 0.2 Vehicle 0.15 0.2 Vehicle 0.15 0.2 SEP-479 SEP-479 SEP-479 SEP-479 SEP-479 SEP-479 (mg/kg) (mg/kg) (mg/kg) (mg/kg) (mg/kg) (mg/kg) © 2026 SEPTERNA 12 CTX: C-terminal telopeptides of type 1 collagen; P1NP: Procollagen type 1 N-terminal propeptide Urinary Calcium (% change over vehicle) Active Vitamin D (% change over vehicle) BMD (% change over vehicle) BMD (% change over vehicle) Serum CTX (% change over vehicle) Serum P1NP (% change over vehicle)
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 • When feedback suppression of endogenous PTH reaches its limits, PTH agonist therapy at higher doses leads to calcium increases SEP-479: 7-day Healthy Cynomolgus Monkey Pharmacodynamic Study 2+ Serum PTH Levels Serum Ca Levels Lessons from PTH peptide clinical trials: • Doses in healthy subjects that increase calcium ~0.5-1 mg/dL translated to relevant therapeutic pharmacology in hypoparathyroidism patients © 2026 SEPTERNA 13
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 across preclinical species (mouse, rat, dog, cyno) • Projected human half-life was approximately 40-80 hours with potential to support QD human dosing Non-clinical safety studies • Generally well tolerated in three non-clinical safety studies (28-day GLP toxicology in rats, dogs, cyno) • Dose-limiting effect in each species was on-target hypercalcemia, as expected for a PTH1R agonist © 2026 SEPTERNA 14
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) and multiple ascending dose (MAD) trial in healthy Endpoints adult volunteers SEP-479 QD x 14 Randomization Safety / tolerability SEP-479 : placebo • Will also include a cross-over food effect study Multiple PK # cohorts TBD 2+ ascending dose PTH, Ca SEP-479 QD x 14 Other biomarkers • Estimated enrollment: up to ~150 subjects (in Australia) SEP-479 QD x 14 SEP-479 dose escalation in healthy volunteers is ongoing: • Observed elimination half-life is ~3-4 days which we believe should support once-daily dosing • MAD cohort dosing duration of 14 days planned to adequately assess steady-state PK Translation of healthy volunteer studies to hypoparathyroidism patients: • Healthy subjects and hypoparathyroidism patients both have intact PTH1R in the bone and kidneys to control serum calcium • Injectable PTH peptide trials: changes in serum calcium translated well from healthy volunteers to hypoparathyroidism patients • On-target pharmacology in Phase 1 to be confirmed initially with decreases in endogenous PTH, and at higher doses, with increases in serum calcium Anticipate SEP-479 SAD / MAD results in Q1 2027 © 2026 SEPTERNA 15
SEP-204: Oral Small Molecule TSHR NAM Targeting TSHR for Graves’ Disease and TED © 2026 SEPTERNA
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 decades • Standard-of-care: antithyroid drugs (ATDs), radioactive iodine, thyroidectomy TED • Develops in ~50% of Graves’ disease patients • Treatments for moderate-to-severe patients include: ® ® • Anti-IGF-1R Abs (TEPEZZA , LUMVOA ): require multiple IV infusions; serious side effects (e.g., hearing loss) ® • Anti–IL-6R Ab (ENSPRYNG ): monthly SC dosing; requires ongoing safety monitoring for infection, liver enzymes, neutropenia Challenge: Each Patient Has Unique Autoantibodies • High-affinity, frequently polyclonal, high titer Our Strategy: TSHR NAM as a potential oral disease- • Ideal medicine would block TSHR activation by all antibodies modifying treatment for all Graves’ disease and TED patients © 2026 SEPTERNA 17 TSHR: Thyroid-stimulating hormone receptor
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 to ATDs for patients who • Address Graves’ and mild TED signs • Address Graves’ and alternative to are intolerant, don’t go into and symptoms existing TED therapies for relapses remission, or relapse; for use prior to • Prevent further TED progression or to avoid side effects thyroidectomy or radioactive iodine A TSHR NAM has the potential to be disease modifying for the entire spectrum of patients with Graves’ disease and TED © 2026 SEPTERNA 18
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 stimulating antibody (TSAb) activation of TSHR in human thyrocyte cell assays Active Highly selective for TSHR (>1000X selective over closely Conformation Inactive related FSHR and LHR) Conformation Demonstrated robust PK/PD and activity in multiple animal models (mice, rats, dogs and monkeys) Excellent pharmaceutical properties; projected human half SEP-204 binds in the transmembrane domain and life should support QD oral dosing prevents TSHR activation, even with TSAb binding Generally well tolerated in GLP toxicology studies Phase 1 trial anticipated to begin in Q1 2027 TSHR © 2026 SEPTERNA 19 TSAb: Thyroid-stimulating antibodies
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
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-204 Exposure SEP-204 (mg/kg) BID SEP-204 (mg/kg) BID • Lower exposures: ↑ TSH to keep T4 • SEP-204 increased TSH in a dose- • SEP-204 decreased T4 levels at the in physiologic range dependent manner (up to >10x) to highest dose after compensatory • Higher exposures: TSHR signaling maintain thyroid hormone T4 levels TSH increases were maximized blunted resulting in ↓ T4 SEP-204 demonstrated a PK/PD response in healthy rats consistent with anticipated HPT axis feedback © 2026 SEPTERNA 21 Note: SEP-204 half life with oral dosing in female rats is ~12 hr. HPT axis: hypothalamic-pituitary-thyroid axis TSH Fold Change T4 Fold Change Fold over Vehicle
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 • Single dose of M22, a Graves’ disease patient-derived thyroid stimulating antibody (TSAb) 0 -36 -24 -12 -8 0 8 16 24 32 40 48 56 • Resulted in rapid increase in thyroid hormone T4 and Time (hr) M22 + Vehicle M22 + 1 mg/kg BID M22 + 3 mg/kg BID M22 + 10 mg/kg BID decrease in TSH levels SEP-204 increased TSH and decreased T4 TSH Endpoint T4 Endpoint 10 2.0 • 1 and 3 mg/kg → T4 normalized to healthy control range 1.5 • 10 mg/kg → T4 suppressed below normal level 1 1.0 0.5 Results suggest that with circulating TSAbs, SEP-204 0.1 0.0 could potentially be dosed to achieve either thyroid . .. 1 3 10 .. .. 1 3 10 Healthy Vehicle Healthy Vehicle Control (+M22) Control (+M22) hormone normalization or suppression (-M22) (-M22) SEP-204 (mg/kg) BID SEP-204 (mg/kg) BID © 2026 SEPTERNA 22 Total T4 (μg/dL) TSH Fold Change Total T4 Fold Change
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 Graves’ Disease Healthy Control Graves’ Mice Graves’ Mice Healthy Control Graves’ Mice Graves’ Mice (-M22) (M22 + vehicle) SEP-204 (100mg/kg) (-M22) (M22 + vehicle) SEP-204 (100mg/kg) • Repeat dosing of M22 (TSAb) x 6 weeks established GD and TED phenotype • Dosing of M22 continued through week 8 during SEP-204 treatment 8 SEP-204 significantly reversed signs 80000 of GD and TED within 2 weeks 70000 6 60000 • T4 was normalized 4 50000 • Thyroid enlargement decreased and 2 40000 thyroid histologic changes were reversed 0 30000 Healthy Ctrl (+M22) 10 30 100 K1-70 HealthyCtrl (+M22) 10 30 100 K1-70 Healthy Vehicle Healthy Vehicle • Orbital proptosis decreased Control (+M22) Control (+M22) SEP-204 mg/kg BID SEP-204 mg/kg BID (-M22) (-M22) © 2026 SEPTERNA 23 3 Volume (mm ) Area (Pixel)
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 • Highly selective for TSHR (>1000x vs. closely related FSHR and LHR) Pharmacokinetics • Demonstrated high oral bioavailability and low clearance across preclinical species (mouse, rat, dog, cyno) • Projected human half-life of ~20-40 hours, which is anticipated to support QD human dosing Preclinical safety studies • Generally well tolerated in 28-day GLP toxicology in rats and dogs; dose-limiting effects were consistent with exaggerated on-target pharmacology (i.e., hypothyroidism) Healthy animal PK/PD studies preview anticipated Phase 1 biomarker readouts • Studies in healthy rats, dogs, and cynomolgus monkeys all demonstrated dose-dependent increases in TSH levels followed by decreases in thyroid hormone levels at higher doses Anticipate SEP-204 Phase 1 trial initiation in healthy volunteers in Q1 2027 © 2026 SEPTERNA 24
SEP-631: Oral Small Molecule MRGPRX2 NAM Targeting MRGPRX2 for Mast Cell-Driven Diseases © 2026 SEPTERNA
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 mediators which cause pain, itch, inflammation, and edema • Pain and itch are driven by mast cells co-localized with sensory neurons • Inflammation and edema are driven by mast cell mediator effects on tissue capillaries leading to vasodilation, vascular permeability, and leukocyte recruitment Targeting MRGPRX2 has the potential to disrupt feedback loops that drive these effects © 2026 SEPTERNA 26
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 binding pocket MRGPRX2 MRGPRX2 Potently inhibits MRGPRX2 activation with an + SEP-631 insurmountable NAM profile • Very high binding affinity (Ki ~0.5 nM) Extracellular view • Slow dissociation rate (t > 2 hours) 1/2 Agonist Locks MRGPRX2 in a state that prevents binding of Extra- binding Agonist pocket cellular Agonist* all agonists, even at high agonist concentrations pocket no longer exists loop • Potent inhibition of MRGPRX2-induced degranulation for both mast cell lines and primary human skin mast cells Transmembrane view PK profile across species projected to once-daily oral dosing in humans © 2026 SEPTERNA 27 *Cortistatin-14
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) dose Safety / tolerability 90 mg P 30 mg L PK H 10 mg n=8 / cohort N L H N P Part B. SEP-631 PO QD for 10 days (MAD) Key endpoints Multiple Randomization SEP-631 dosing L 12:4 L ascending Safety / tolerability 200 mg QD x 9 days (SEP-631:placebo) 90 mg dose PK 30 mg 10 mg PD: skin challenge n=16 / cohort Skin Challenge Objective (Post-dose) H H Part C. SEP-631 PO single dose crossover P L H Key endpoints L = icatibant 10 µg/mL 5-day washout Randomized 200 mg 200 mg N H = icatibant 100 µg/mL L Food effect open-label H Fasted Fasted N = negative control (saline) crossover Safety / tolerability P = positive control (histamine) 200 mg 200 mg n=8 PK (fasted vs fed) Fed Fed Phase 1 Results • Safety: No severe or serious events; rate of adverse events with SEP-631 was comparable with placebo • Pharmacokinetics: Elimination half-life is approximately 24 hours, supporting once-daily (QD) dosing • Food effect study: Similar exposure in fed and fasted conditions supports QD dosing without food restrictions • Pharmacodynamics: Robust inhibition of icatibant-induced skin wheal formation © 2026 SEPTERNA 28
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 inhibition at 90 and 200 mg QD Icatibant 10 µg/mL Icatibant 100 µg/mL Receptor occupancy Receptor occupancy at trough drug levels at trough drug levels ~94% ~97% ~99% >99% ~94% ~97% ~99% >99% Nominal p-values comparing each SEP-631 dose level to placebo for change from baseline are based on an ANCOVA © 2026 SEPTERNA 29 model including a fixed effect for treatment group and baseline wheal response as a covariate
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 MRGPRX2 inhibition • Subnanomolar binding affinity (Ki ~0.5 nM) with slow receptor off-rate kinetics (t > 2 hours) 1/2 • Completely closes MRGPRX2 agonist binding pocket, preventing agonist binding Robust clinical pharmacodynamic effects • High receptor occupancy (>99%) translated into full inhibition of icatibant-induced skin wheal formation in Phase 1, and similarly high levels of MRGPRX2 inhibition in target tissues throughout the body may be needed for optimal efficacy for mast cell-driven diseases Clean clinical safety profile • No severe or serious events observed; rate of adverse events with SEP-631 was comparable with placebo Convenient, once-daily oral tablet with a flexible dosing schedule • Elimination half-life ~24 hours; no food effect © 2026 SEPTERNA 30
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 clinical studies Focus on indications characterized by: • Diseases where mast cells are believed to play a central role • Diverse pathologies to test various therapeutic hypotheses • Significant unmet need © 2026 SEPTERNA 31
Metabolic Programs Oral Small Molecule Programs Targeting GLP-1R, GIPR, GCGR and Other Targets for Obesity, Diabetes, and Other Cardiometabolic Diseases © 2026 SEPTERNA
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 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 Collaboration Objective: discover, develop and product sales commercialize multiple novel mono-, dual-, or • Opt-in right for worldwide profit-share for one program triple-acting oral small molecule drug candidates directed to obesity, type 2 diabetes and other Novo responsible for coverage of all collaboration cardiometabolic diseases R&D expenses © 2026 SEPTERNA 33
Building a World-Class GPCR-Focused Biotechnology Company © 2026 SEPTERNA
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 Board of Directors Academic Co-Founders • Jeff Finer, MD, PhD, CEO • Robert J. Lefkowitz, MD, Duke University Medical Center • Arthur Christopoulos, PhD, Monash University • Jeff Tong, PhD, Third Rock Ventures • Patrick Sexton, PhD, DSc, Monash University • Alan Ezekowitz, MD, DPhil, Third Rock Ventures • Abe Bassan, Samsara BioCapital Drug Discovery Advisory Board • Jake Simson, PhD, RA Capital • Ruth Wexler, PhD, formerly with BMS • Bernard Coulie, MD, PhD, MBA, Independent Director • John Lowe, PhD, formerly with Pfizer • Shalini Sharp, MBA, Independent Director • Craig Lindsley, PhD, Vanderbilt, formerly with Merck • Keith Gottesdiener, MD, Independent Director • Tom Baillie, PhD, DSc, formerly with Merck • David Lacey, MD, formerly with Amgen © 2026 SEPTERNA 35
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 multi- data in Q12027 Agonist billion $ market opportunity SEP-204 (TSHR) Anticipate Phase 1 initiation in Q1 2027 ® Negative Allosteric Modulator • Native Complex Platform drives rapid compound identification and portfolio SEP-631 (MRGPRX2) expansion Negative Allosteric Modulator PTH1R Program • Well-capitalized with cash runway Agonist (for Osteoporosis) expected to support operating plans at least into 2029 Partnered Programs Partner Obesity and Other Metabolic Programs Cardiometabolic GLP-1R, GIPR, GCGR* Diseases © 2026 SEPTERNA 36 * Partnership also includes two undisclosed targets
Pioneering a New Era of GPCR Drug Discovery © 2026 SEPTERNA