Full Press Release Details
Healthcare Conference 2026 January 2026 Nasdaq: SEPN
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,
including our 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 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. 2026 SEPTERNA 2
Septerna: Pioneering a New Era Lead Programs of GPCR Drug Discovery with
SEP-479 PTH1R Agonist: Potential first-in-class oral small molecule for hypoparathyroidism; Phase 1 Oral Small Molecules clinical trial initiation anticipated in 1H 2026 Native Complex Platform designed to SEP-631 MRGPRX2 NAM: Pipeline-in-a-product
unlock the full potential of GPCR therapies opportunity for mast cell-driven diseases (e.g., CSU); Phase 1 SAD/MAD results anticipated at AAAAI Iterative structure-based drug design to rapidly Annual Meeting in March 2026 optimize and validate
programs in animal models Portfolio strategy to drive value creation Discovery Stage Validated targets + early clinical readouts + multi-billion $ market opportunities TSHR NAM: Potential disease-modifying treatment for Graves' disease and
TED; progressing multiple lead Well-capitalized compounds toward development candidate selection Cash runway expected to support operating plans at Incretin Receptor Agonists: Potential multi-billion $ least into 2029 collaboration with Novo Nordisk
for oral small molecules for metabolic diseases 2026 SEPTERNA GPCR: G protein-coupled receptor; NAM: negative allosteric modulator; TED: thyroid eye disease; CSU: chronic spontaneous urticaria; AAAAI: American Academy of Allergy, Asthma &
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
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 / US Patient Population * Phase 1 initiation Anticipate Phase 1 Endocrinology SEP-479 (PTH1R) anticipated in
topline data in Hypoparathyroidism: ~70k 1H 2026 late 2026 / early 2027 Agonist Immunology and Inflammation SAD/MAD presentation SEP-631 (MRGPRX2) planned in CSU: ~1.5mm March 2026 Negative Allosteric Modulator Other mast cell diseases Endocrinology
TSHR Program Graves' disease: ~2mm Negative Allosteric Modulator Thyroid eye disease: ~1mm 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 + Undisclosed Undisclosed Undisclosed * Pending successful completion of regulatory submissions 2026 SEPTERNA 6
SEP-479: Oral Small Molecule PTH1R Agonist Targeting PTH1R for
Hypoparathyroidism 2026 SEPTERNA
Hypoparathyroidism: Significant Unmet Need for an Oral PTH Replacement
Hypoparathyroidism: Low PTH leads to low blood calcium PTH: Master Regulator of 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
Native Complex Platform Identified Portfolio of PTH1R Agonists with
Potential to Address Significant Unmet Need in Hypoparathyroidism Native Complex Hit Native Complex Structure-Based Identification Design and Optimization Multiple PTH1R agonists Multiple PTH1R agonist with distinct binding sites series optimized in
parallel SEP-479 Next-generation oral small molecule Multiple Compounds PTH1R agonist candidate PTH with Candidate Potential Structurally unrelated to first clinical candidate (SEP-786) which was Potent, selective, oral small
discontinued in Phase 1 due to off- molecules Rapid Iterative target hyperbilirubinemia Structure-Based Normalized serum calcium in PTH1R Drug Discovery Monkey PK/PD study demonstrated preclinical animal models robust decreases in
endogenous PTH Demonstrated comparable effects and increases in serum calcium to PTH peptides in cell-based Excellent pharmaceutical properties; assays and animal models projected to achieve full-day calcium <1 year from
initiation of control with QD dosing medicinal chemistry to G protein activity in an animal model 2026 SEPTERNA PK: Pharmacokinetics PD: Pharmacodynamics 9
SEP-479: A Potent, Selective PTH1R Agonist Normalized Serum Calcium and
Phosphate in Hypoparathyroidism Animal 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 PO: oral dosing QD: once daily dosing BID: twice daily dosing 10
SEP-479: Preclinical Studies Demonstrated Favorable Oral Small Molecule
Candidate Profile SEP-479: 7-day Healthy Cynomolgus Monkey Pharmacodynamic Study 2+ Serum PTH Levels Serum Ca Levels 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 relevant 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 2026 SEPTERNA 11
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 2026 SEPTERNA 12
SEP-631: Oral Small Molecule MRGPRX2 NAM Targeting MRGPRX2 for Mast
Cell-Driven Diseases, Including CSU 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 2026 SEPTERNA 14
SEP-631: Clinical-Stage MRGPRX2 NAM with Potentially Differentiated
Profile for Mast Cell-Driven Diseases Preclinical Profile: Key Criteria for Advancement SEP-631 Complete High Potency High potency observed in multiple functional and binding assays Insurmountable inhibition of multiple endogenous agonists; long
receptor residence time Broad Inhibition demonstrated in biophysical assays Excellent oral bioavailability in preclinical models; PK profile across species supports QD Oral PK Profile 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 Non-Clinical Safety: 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 2026 SEPTERNA 15
SEP-631 Inhibited MRGPRX2 Activation in Translational Models SEP-631
Potently Inhibited Skin Extravasation in MRGPRX2 Knock-in SEP-631 Potently Inhibited Primary Mouse Model Human Skin Mast Cell Degranulation Knock-in Mouse Complete Inhibition of Skin mMRGPRB2 KO Extravasation with SEP-631 hMRGPRX2 KI Treat with oral
MRGPRX2 NAM (SEP-631) or vehicle Administer Evans Blue dye Intradermal skin challenge with Cortistatin-14 (MRGPRX2 agonist) Measure extravasation of dye into skin Primary human skin mast cells from skin donors stimulated with Substance P
Extravasation No extravasation (no MRGPRX2 inhibition) (MRGPRX2 inhibition) SEP-631 potently inhibited tryptase release KO: gene knockout KI: gene knock-in 2026 SEPTERNA 16
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) Skin Challenge Objective (Post-dose) SEP-631 dosing L L H H N QD x 9 days N P P L = low-dose icatibant; H = high-dose icatibant; N = negative control (saline); P = positive control
(histamine) AAAAI: American Academy of Allergy, Asthma & Immunology 2026 SEPTERNA 17
TSHR NAM Program Oral Small Molecule Targeting TSHR for Graves'
Disease and TED 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 2026 SEPTERNA 19
Oral Small Molecule TSHR NAMs Reversed Symptoms in Novel Graves'
Disease Model TSHR Activating TSHR Activating Ab Selective TSHR NAMs Antibody +TSHR NAM Thyroid Hormone Levels Reversal of Thyroid and Thyroid Size Eye Manifestations Blocked activation of TSHR by patient- Eye
Proptosis (bulging) 6 weeks 1 week Mouse derived autoantibodies Isotype mAb control + Vehicle Insurmountable NAM profiles in cell- based assays Preclinical Leads Inhibited Diverse Patient Autoantibodies Agonist mAb + Vehicle Fully
inhibited several Graves' patient polyclonal serum samples in primary orbital fibroblasts Agonist mAb + SP-1351 Reversed Graves' Animal Disease Model Effects Normalization of thyroid hormone T4 Reduction in thyroid weight
Reversal of proptosis Lead optimization is ongoing towards selection of a development candidate 2026 SEPTERNA 20
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 Nordisk 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 Collaboration Objective: discover, develop Mid-to-high
single-digit tiered royalties based on global and commercialize multiple novel mono-, dual-, product sales or triple-acting oral small molecule drug Opt-in right for worldwide profit-share for one program candidates directed to obesity, type
2 diabetes and other cardiometabolic diseases Novo responsible for coverage of all collaboration R&D expenses 2026 SEPTERNA 22
Building a World-Class GPCR-Focused Biotechnology Company 2026