Septerna, Inc. · NASDAQ:SEPN
Septerna — Investor Presentation (April 2026)
41 slides from Septerna's investor presentation, Apr 13, 2026
Slide 1: Pioneering a New Era of GPCR Drug Discovery
Pioneering a New Era of GPCR Drug Discovery April 2026 Nasdaq: SEPN Corporate Presentation Exhibit 99.2
Slide 2: Forward-Looking Statements
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 conta
Slide 3: Septerna: Pioneering a New Era of GPCR Drug Discovery with Oral Small Molecules
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
Slide 4: GPCR Drug Discovery Success Has Been Highly Concentrated to a Small Fraction of GPCRs
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 approve
Slide 5: Proprietary 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 Lig
Slide 6: Advancing a Deep Portfolio of Oral Small Molecule GPCR-Targeted Programs
Advancing a Deep Portfolio of Oral Small Molecule GPCR-Targeted Programs * Pending successful completion of regulatory submissions Wholly-Owned Programs Development Status a Program / Target Mode of Action Therapeutic Area Indications / US Patient Population Discovery IND-enabling Phase 1 Phase 2 SE
Slide 7: Targeting PTH1R for Hypoparathyroidism SEP-479: Oral Small Molecule PTH1R Agonist
Targeting PTH1R for Hypoparathyroidism SEP-479: Oral Small Molecule PTH1R Agonist
Slide 8: Hypoparathyroidism: Significant Unmet Need for an Oral PTH Replacement
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 Standa
Slide 9: SEP-479: Discovered with Native Complex Platform as Potent Oral PTH1R Agonist
SEP-479: Discovered with Native Complex Platform™ as Potent Oral PTH1R Agonist for Hypoparathyroidism Multiple PTH1R agonists with distinct binding sites identified and optimized in parallel to candidate quality molecules Native Complex Hit Identification and Structure-Based Optimization Rapid Itera
Slide 10: SEP-479 Normalized Serum Calcium and Phosphate in Rat Hypoparathyroidism Model
SEP-479: A Potent PTH1R Agonist Normalized Serum Calcium and Phosphate in Rat Hypoparathyroidism Model PO: oral dosing QD: once daily dosing BID: twice daily dosing Surgery to remove parathyroid glands Rat Decreased serum calcium (hypocalcemia) Oral small molecule PTH1R agonist Normalize serum calci
Slide 11: SEP-479 Lowered Endogenous PTH and Increased Serum Calcium in Cynomolgus Monkey Study
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 W
Slide 12: SEP-479 Preclinical Profile Supported Advancement into Phase 1
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 acro
Slide 13: SEP-479 Phase 1 Study in Healthy Volunteers is in Progress
SEP-479 Phase 1 Study in Healthy Volunteers is in Progress Study design: Randomized, placebo-controlled, single ascending dose (SAD) and multiple ascending dose (MAD) trial in healthy adult volunteers Will also include a cross-over food effect study Estimated enrollment: up to ~150 subjects (in Aust
Slide 14: Targeting MRGPRX2 for Mast Cell-Driven Diseases SEP-631: Oral Small Molecule MRGPRX2 NAM
Targeting MRGPRX2 for Mast Cell-Driven Diseases SEP-631: Oral Small Molecule MRGPRX2 NAM
Slide 15: MRGPRX2 is a Key Regulator of Mast Cell Degranulation
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 mediator
Slide 16: SEP-631: MRGPRX2 NAM with a Potentially Differentiated Profile
SEP-631: MRGPRX2 NAM with a Potentially Differentiated Profile for Mast Cell-Driven Diseases SEP-631 is a negative allosteric modulator (NAM) Binds to a novel allosteric site, distinct from the agonist binding pocket Potently inhibits MRGPRX2 activation with an insurmountable NAM profile Very high b
Slide 17: SEP-631 Inhibited MRGPRX2 Activation in Humanized Mouse Translational Model
SEP-631 Inhibited MRGPRX2 Activation in Humanized Mouse Translational Model KO: gene knockout KI: gene knock-in SEP-631 Potently Inhibited Skin Extravasation Treat with oral MRGPRX2 NAM (SEP-631) or vehicle Administer Evans Blue dye Measure extravasation of dye into skin Extravasation (no MRGPRX2 in
Slide 18: SEP-631 Preclinical Profile
SEP-631 Preclinical Profile SEP-631 Preclinical Data Supports Potential Best-in-Class Profile Subnanomolar binding affinity and slow off-rate kinetics Insurmountable negative allosteric modulator mechanism closes off agonist binding pocket Inability to activate receptor despite presence of high dose
Slide 19: SEP-631 Phase 1 Study Design
SEP-631 Phase 1 Study Design Goal: Evaluate the safety, tolerability, PK, PD (with an icatibant skin challenge), and food effects 120 healthy adult volunteers, double-blind, randomized, and placebo-controlled SAD/MAD study design 10 mg 30 mg 90 mg 200 mg 300 mg 400 mg Single ascending dose n=8 / coh
Slide 20: SEP-631: Adverse Event Profile Comparable to Placebo and PK Support Once-Daily Dosing
SEP-631: Adverse Event Profile Comparable to Placebo and Pharmacokinetics Support Once-Daily Oral Dosing Pharmacokinetics Elimination half-life of SEP-631 is approximately 24 hours, supporting once-daily (QD) dosing Food Effect Study SEP-631 with high-fat, high-calorie meal resulted in similar expos
Slide 21: Pharmacodynamics Assessed Using an Icatibant Skin Challenge
Pharmacodynamics Assessed Using an Icatibant Skin Challenge Icatibant is a selective MRGPRX2 agonist that induces a skin wheal response following intradermal injection Skin challenge performed at baseline (Day –1) and steady-state (Day 9) following SEP-631 or placebo treatment Skin challenge agents:
Slide 22: SEP-631 Inhibits Icatibant Wheal Formation in Dose-Dependent Manner
SEP-631 Inhibits Icatibant Wheal Formation in Dose-Dependent Manner to Complete Inhibition Nominal p-values comparing each SEP-631 dose level to placebo for change from baseline are based on an ANCOVA model including a fixed effect for treatment group and baseline wheal response as a covariate SEP-6
Slide 23: SEP-631 Preclinical Profile Translated Well to Phase 1 Clinical Trial Results
SEP-631 Preclinical Profile Translated Well to Phase 1 Clinical Trial Results SEP-631 Preclinical Profile Robust SEP-631 Phase 1 Results Subnanomolar binding affinity Slow receptor off-rate kinetics Target Coverage Estimated high receptor occupancy (>99%) Excellent oral PK across preclinical species
Slide 24: SEP-631: Initial Phase 2 Development Strategy
SEP-631: Initial Phase 2 Development Strategy Broad opportunity across a range of allergic and inflammatory diseases where mast cells are implicated in disease pathophysiology Mast cells reside in organ systems throughout the body contributing to pain, itch, and inflammation Our Strategy: since the
Slide 25: Chronic Spontaneous Urticaria (CSU): High Disease Burden, Large Patient Population
Chronic Spontaneous Urticaria (CSU): High Disease Burden, Large Patient Population CSU is an undertreated dermatology condition characterized by itchy and painful wheals and angioedema Significant burden of disease; patients experience1: Disease Burden % CSU Patients High to very high impact on thei
Slide 26: Plan to Initiate Phase 2b Dose-Ranging CSU Study in 2H 2026
Plan to Initiate Phase 2b Dose-Ranging Chronic Spontaneous Urticaria Study in 2H 2026 Long-term GLP toxicology studies in rats and dogs to be completed by mid-year 2026 Planned global, randomized, double-blind, placebo-controlled study to evaluate safety and exploratory efficacy of SEP-631 in CSU Ra
Slide 27: Exploring Opportunities for SEP-631 in Additional Indications with High Unmet Need
Atopic Dermatitis Interstitial Cystitis Migraine Asthma Exploring Opportunities for SEP-631 in Additional Indications with High Unmet Need Indications characterized by mast cells playing a central role in disease pathology and evidence of MRGPRX2 expression on tissue-resident mast cells Indications
Slide 28: Oral Small Molecule Targeting TSHR for Graves' Disease and TED
Oral Small Molecule Targeting TSHR for Graves’ Disease and TED TSHR NAM Program
Slide 29: No Disease-Modifying Therapies for Graves' Disease and Thyroid Eye Disease
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,
Slide 30: Oral Small Molecule TSHR NAMs Reversed Symptoms in Novel Graves' Disease Model
Oral Small Molecule TSHR NAMs Reversed Symptoms in Novel Graves’ Disease Model Selective TSHR NAMs Blocked activation of TSHR by patient-derived autoantibodies Insurmountable NAM profiles in cell-based assays Preclinical Leads Inhibited Diverse Patient Autoantibodies Fully inhibited several Graves’
Slide 31: Oral Small Molecule Programs Targeting GLP-1R, GIPR, GCGR for Cardiometabolic Diseases
Oral Small Molecule Programs Targeting GLP-1R, GIPR, GCGR and Other Targets for Obesity, Diabetes, and Other Cardiometabolic Diseases Metabolic Programs
Slide 32: Collaboration with Novo Nordisk for Oral Small Molecules for Metabolic Diseases
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 P
Slide 33: Building a World-Class GPCR-Focused Biotechnology Company
Building a World-Class GPCR-Focused Biotechnology Company
Slide 34: Proven Leaders in GPCR Drug Development and Company Building
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 Fi
Slide 35: Septerna: Pioneering a New Era of GPCR Drug Discovery
Septerna: Pioneering a New Era of GPCR Drug Discovery Portfolio of oral small molecule GPCR-targeted programs Multi-product pipeline, each with a multi-billion $ market opportunity Native Complex Platform® drives rapid compound identification and portfolio expansion Well-capitalized with cash runway
Slide 36: Pioneering a New Era of GPCR Drug Discovery
Pioneering a New Era of GPCR Drug Discovery
Slide 37: Appendix
Appendix
Slide 38: Safety: Single Dose Adverse Event Profile Comparable to Placebo
Safety: Single Dose Adverse Event Profile Comparable to Placebo Rate of TEAEs with SEP-631 was comparable with placebo No severe or serious events were reported 2 AEs of mild transaminase elevations (<1.5x ULN) observed with SEP-631 were not related to dose, and at rates comparable to placebo TEAE,
Slide 39: Safety: Multiple Dose Adverse Event Profile Comparable to Placebo
Safety: Multiple Dose Adverse Event Profile Comparable to Placebo Rate of TEAEs with SEP-631 was comparable with placebo. No severe or serious events were reported One mild transaminase elevation (<1.5x ULN) observed with SEP-631 and one observed with placebo TEAE, treatment-emergent adverse event a
Slide 40: Native Complex Platform is a Highly Efficient Platform for GPCR Structure-Based Drug Design
Native Complex Platform® is a Highly Efficient Platform for GPCR Structure-Based Drug Design 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
Slide 41: SEP-786: First Clinical PTH1R Agonist Discontinued in Phase 1 in February 2025
SEP-786: First Clinical PTH1R Agonist Discontinued in Phase 1 in February 2025 Due to Unanticipated Events SEP-786 Phase 1 SAD/MAD trial in healthy volunteers discontinued 2 unanticipated severe (Grade 3) events of elevated unconjugated bilirubin levels in MAD Both events were reversible and without