Full Press Release Details
Healthcare Conference 2025 January 2025 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 milestones and objectives of management are forward-looking statements. Such forward-looking statements include, but are not
limited to, statements regarding: the continued development and advancement of our oral small molecule GPCR-targeted programs; the initiation, timing, progress, and results of conducting our research and development programs and our current and
future preclinical studies and anticipated clinical trials, and the release of data related thereto; our ability to demonstrate, and the timing of, preclinical proof-of-concept in vivo and ex vivo for multiple programs; the potential of our
proprietary Native Complex Platform ; the accuracy of our estimates regarding expenses and capital requirements, including our expected cash runway; the size and growth potential of the markets for our current and future product candidates and our
ability to serve those markets; and our expectations regarding the implementation of our business model, and strategic plans for our business, product candidates, and technology. Such forward- looking statements reflect the current views of the
Company and are subject to known and unknown risks and other factors, which are, in some cases, beyond the Company's control. Risks that contribute to the uncertain nature of the forward-looking statements include those risks and uncertainties
set forth in the section titled Risk Factors in our most recent Quarterly Report on Form 10-Q for the quarter ended September 30, 2024, filed with the Securities and Exchange Commission (the "SEC") and in our subsequent filings with the
SEC. Certain information in this presentation (including market data and statistical information) and statements made orally during this presentation are the good faith estimates of management and have been obtained from various sources (including
third-party sources such as independent industry publications, governmental publications, and reports by market research firms), and we do not guarantee the accuracy or completeness of such information. No representations or warranties (expressed or
implied) are made about the accuracy of such forward-looking statements, and there can be no assurance as to the reliability or correctness of such projections and actual results may vary materially from those projected. The Company undertakes no
obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made. 2025 SEPTERNA 2
Septerna: Pioneering a New Era Lead Candidates of GPCR Drug Discovery
with SEP-786 PTH1R Agonist: Potential first-in-class oral Oral Small Molecules small molecule for hypoparathyroidism; Phase 1 underway with SAD/MAD data expected in mid-2025 SEP-631 MRGPRX2 NAM: Pipeline-in-a-product Native Complex Platform designed
to opportunity for mast cell diseases (e.g., CSU); Phase 1 unlock the full potential of GPCR therapies initiation expected in 2025 Iterative structure-based drug design to rapidly optimize and validate programs in animal models Portfolio strategy to
drive value creation Discovery Stage Validated targets + early clinical readouts + TSHR NAM: Potential first disease-modifying treatment for Graves' disease and TED multi-billion $ market opportunities Incretin Receptor Agonists: Opportunities
for Well capitalized with a planned operating single- and multi-incretin receptor agonists for runway into 2H 2027 metabolic diseases (e.g., obesity and T2D) 2025 SEPTERNA GPCR = G protein-coupled receptor; NAM = negative allosteric
modulator; TED = thyroid eye disease; CSU = chronic spontaneous urticaria; T2D = Type 2 diabetes 3
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 2025 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
Native Complex Platform is a Highly Efficient Platform for GPCR
Structure-based Drug Design 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) Native Complex Cryo-EM Native Complex High-Resolution GPCR Structures 24 ~1-2 weeks Agonist 20 Positive Allosteric Modulator Antagonist Rapid New Small New Ligand-Bound Negative Allosteric
Modulator 16 Apo (no ligand) Iterative Molecule Ligand GPCR Structure 12 Cycle 8 Structure-Based Design 4 GPCR A B C D E F G 2025 SEPTERNA cryo-EM = cryogenic electron microscopy 6 # Structures
Advancing a Deep Portfolio of Oral Small Molecule GPCR-Targeted Programs
Programs Development Status Program / Target Therapeutic Area Discovery IND-enabling Phase 1 Phase 2 Phase 3 Mode of Action Indications / US Patient Population Endocrinology SEP-786 (PTH1R) Hypoparathyroidism: ~70k Agonist Immunology and
Inflammation SEP-631 (MRGPRX2) CSU: ~1.5mm Negative Allosteric Modulator Other mast cell diseases Endocrinology TSHR Graves' disease: ~2mm Negative Allosteric Modulator Thyroid eye disease: ~1mm Metabolic Diseases GLP-1R, GIPR, GCGR Obesity
and T2D: ~800mm (worldwide) Single- and Multi-Agonists Other metabolic diseases Other Therapeutic Areas of Interest / Focus: Neurology, Women's Health, Cardiovascular Disease and Respiratory Disease Note: Vertex acquired an undisclosed
discovery-stage program in 2023 for $47.5M upfront 2025 SEPTERNA 7
SEP-786: Oral Small Molecule PTH1R Agonist Targeting PTH1R for
Hypoparathyroidism 2025 SEPTERNA
Hypoparathyroidism: Significant Unmet Need for an Oral PTH Replacement
Hypoparathyroidism: Low PTH leads to low blood PTH: Master Regulator of Blood Calcium calcium ~70K patients in US; ~140K patients in EU Challenging patient symptoms Muscle cramps, tingling, brain fog Life-threatening
complications: cardiac arrhythmias, seizures Inadequate standard-of-care Calcium supplements (high doses several times per day) and Vitamin D do not fully resolve symptoms, and lead to complications including calcifications and renal
impairment Injectable PTH therapies approved and in development Will require life-long injections Our Strategy: Develop oral PTH1R agonist Functionally replace PTH with oral small molecule to normalize serum calcium 2025 SEPTERNA 9
PTH = Parathyroid Hormone
SEP-786: Product of Our Native Complex Platform Drug Discovery Native
Complex Native Complex Native Complex Hit Identification Structure-Based Design Lead Optimization Led to SEP-786 Multiple PTH1R agonists Multiple PTH1R agonist with distinct binding sites series optimized in parallel SEP-786 Potent,
selective oral small molecule Rapid Iterative Normalized serum calcium in Structure-Based PTH1R preclinical model Drug Discovery PK/PD model projects full-day calcium control with QD or BID dosing <1 year from initiation of
Currently in Phase 1 clinical trial medicinal chemistry to activity in an animal model 2025 SEPTERNA QD = once-daily dosing BID = twice-daily dosing PK = pharmacokinetics PD = pharmacodynamics 10
SEP-786 Demonstrated Potent, Selective Activation of PTH1R and
Dose-dependent Serum Calcium Increases Rat surgical model of hypoparathyroidism Single-dose 28-day dosing 2+ Matches efficacy of peptide Sustained Ca control 4 4 Vehicle (PO) Rat Vehicle (PO) SEP-786 (PO, 3 mg/kg BID) 3 3 SEP-786 (PO, 3 mg/kg) 2+
Normal serum Ca range Surgery to remove SEP-786 (PO, 10 mg/kg) parathyroid glands SEP-786 (PO, 30 mg/kg) 2 2 4 LA-PTH (SC, 2 nmol/kg) 2+ Normal serum Ca range Decreased serum Vehicle (PO) 1 1 calcium (hypocalcemia)3 0 6 12 SEP- 18 786 (PO, 3 24
mg/kg) 4 Time (hr) SEP-786 (PO, 10 mg/kg) Day 1 Day 10 Day 19 Day 28 4 Vehicle (PO) SEP-786 (PO, 30 mg/kg) 2 PTH1R agonist Vehicle (PO) 3 SEP-786 (PO, 3 mg/kg) LA-PTH (SC, 2 nmol/kg) (SEP-786) SEP-786 (PO, 3 mg/kg BID) 2+ SEP-786 (PO, 10 mg/kg) 3
Normal serum Ca range 2+ 1 Normal serum Ca range SEP-786 (PO, 30 mg/kg) 2 0 6 12 18 24 Normalize LA-PTH (SC, 2 nmol/kg) serum calcium Time (hr) 2 2+ Normal serum Ca range 1 0 6 12 18 24 1 Time (hr) 2025 SEPTERNA PO = oral dosing SC =
subcutaneous dosing 11 Day 1 Day 10 Day 19 Day 28 6h 9h 18h 24h 6h 9h 6h 18h 9h 24h 18h 24h 6h 9h 6h 18h 9h 24h 18h 24h 6h 9h 6h 18h 9h 24h 18h 24h 6h 9h 18h 24h 2+ Serum Ca level (mmol/L) 2+ Serum Ca level (mmol/L) 2+ Serum Ca level (mmol/L) 2+
Serum Ca level (mmol/L) 2+ Serum Ca level (mmol/L)
SEP-786: Phase 1 Trial Underway, Data Expected Mid-2025 Preclinical
data supports clinical development PK studies in mice, rats, dogs, and monkeys support predicted human PK for QD or BID dosing 28-day GLP toxicology studies in rats and dogs: generally well-tolerated Effects of
exaggerated on-target pharmacology seen at high doses Phase 1 clinical trial underway - data anticipated mid-2025 Single-ascending dose (SAD) & multiple-ascending dose (MAD) trial in healthy volunteers MAD portion to assess
both QD and BID dosing Primary endpoints: safety and tolerability Secondary endpoints: PK, serum calcium, other biomarkers 2025 SEPTERNA 12
SEP-631: Oral Small Molecule MRGPRX2 NAM Targeting MRGPRX2 for Mast
Cell Disorders, Including CSU 2025 SEPTERNA
MRGPRX2: Emerging Target for Mast Cell-Driven Diseases MRGPRX2
Highly and uniquely expressed on mast cells Distinct from IgE / allergen pathway Multiple endogenous agonists Mast Cell-Driven Diseases CSU, atopic dermatitis, allergic asthma, and others CSU: Significant Unmet Need
~1.5 million patients in US Itchy, painful hives and angioedema Chronic symptoms can impact quality of life First-line treatment: antihistamines; 37% refractory Second-line treatment: anti-IgE (Xolair); 64% refractory
Our Strategy: MRGPRX2 NAM Inhibit mast cell activation by selectively blocking MRGPRX2 NAM= Negative Allosteric Modulator 2025 SEPTERNA 14
SEP-631: Oral Small Molecule MRGPRX2 NAM Designed to Stop
MRGPRX2-Mediated Mast Cell Degranulation SEP-631: Selective MRGPRX2 NAM Knock-in Mouse mMRGPRB2 KO hMRGPRX2 KI Potent oral small molecule SEP-631 Potently Inhibited Skin Treat with oral MRGPRX2 Blocked activation of all endogenous
Extravasation in MRGPRX2 NAM (SEP-631) or vehicle MRGPRX2 activators Knock-in Model Showed insurmountable NAM profile Administer Evans Blue dye p < 0.05 with long-lasting inhibition 8 Intradermal skin challenge with Cortistatin-14
Effective in Preclinical Models (MRGPRX2 agonist) 6 Prevented skin extravasation in human Measure 4 MRGPRX2 knock-in mouse extravasation of dye into skin Potently inhibited degranulation of 2 primary human mast cells vehicle
Demonstrated good PK properties and 0 0 3 has been generally well tolerated in Extravasation No extravasation SEP-631 (mg/kg, PO) (no MRGPRX2 inhibition) (MRGPRX2 inhibition) preclinical safety models to date 2025 SEPTERNA 15 Skin Evans Blue
extravasation (fold over vehicle)
SEP-631: MRGPRX2 NAM with Potentially Differentiated Profile Key
Criteria SEP-631 High Potency Demonstrated in multiple functional and binding assays Broad Inhibition Long residence time and insurmountable inhibition of multiple endogenous agonists Excellent oral bioavailability; PK profile across species
supports QD oral dosing Good Oral PK projection in humans In vitro PD Activity in primary human skin mast cells In vivo PD Activity in hMRGPRX2 knock-in mice Favorable in vivo safety profile 14-day non-GLP studies in rat and dog showed a generally
favorable tolerability profile IND-enabling studies ongoing to support advancement into Phase 1 clinical trial in 2025 2025 SEPTERNA 16
TSHR NAM Program 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)
Drug Discovery Challenge: Each Patient Has Unique Autoantibodies High-affinity, frequently polyclonal, high titer Our Strategy: TSHR NAM Oral disease-modifying treatment for all Graves' disease and TED patients NAM= Negative Allosteric
Modulator 2025 SEPTERNA 18
Oral Small Molecule TSHR NAMs Reversed Symptoms in Novel Graves'
Disease Model Selective TSHR NAMs TSHR Activating TSHR Activating Ab Blocked activation of TSHR by Antibody +TSHR NAM Thyroid Hormone Levels patient-derived autoantibodies Reversal of Thyroid and Thyroid Size Eye Manifestations
6 weeks 1 week Eye Proptosis (bulging) Demonstrate insurmountable profiles Mouse Isotype mAb control + Vehicle Preclinical Leads Inhibited Diverse Patient Autoantibodies 1500 0.3 Fully inhibited several Graves' patient
polyclonal serum samples in primary 1000 0.2 Agonist mAb + Vehicle orbital fibroblasts 500 0.1 Reversed Graves' Animal Disease Model Effects Agonist mAb + SP-1351 0 0.0 Normalization of thyroid hormone T4 Reduction in thyroid
weight Reversal of proptosis 2025 SEPTERNA 19 mAb = monoclonal antibody Vehicle Agonist mAb + Vehicle Agonist mAb + SP-1351 Vehicle Agonist mAb + Vehicle Agonist mAb + SP-1351 Plasma T4 Levels (pg/dL) Thyroid Weight (g)
Oral Small Molecule Incretin Receptor Agonist Programs Single- and
Multi-GLP-1R, GIPR, and GCGR Agonists for Metabolic Disorders, Including Obesity and Type 2 Diabetes 2025 SEPTERNA
Next-Generation Oral Incretin Receptor Agonists Incretin peptide
therapeutics have been transformative Our Strategy: Next-generation treatments for obesity and diabetes incretin receptor agonists Marketed GLP-1 and GLP-1/GIP products generated ~$36B in global Oral small molecule single- and multi-incretin
receptor agonists sales in 2023 that can be used as single medicines or in combination Limitations: tolerability, injection administration, prolonged titration schemes Novel binding pocket identified with potential to develop both
Approximate % sequence similarity across GLP-1R, GIPR, CGCR single- and multi-incretin receptor agonists Septerna Binding Site Pocket has higher sequence similarity across GLP-1R, GIPR, GCGR 80 - 90% vs. than known binding sites occupied by
clinical-stage GLP-1R small Danuglipron & Orforglipron Sites molecule agonists 40 - 60% 2025 SEPTERNA 21
Discovery of Oral Small Molecule Single- and Multi-Incretin Receptor
Agonists Example: Selective mono-GIPR agonists demonstrated weight loss both Identified Multiple Incretin Receptor alone and with additive activity in combination with a GLP-1 peptide Agonist Chemical Series Diet-induced obese (DIO) mouse
model +/- semaglutide Activity spans combinations of activities 110 across GLP-1R, GIPR, and GCGR QD dosing 100 p < 0.05 Optimizing Both Single- and Multi- Vehicle (PO) ~7% Vehicle (SC) Incretin Agonist Leads Focused on: 90 SP-2991 (PO,
30 mg/kg) Vehicle (SC) Mono-GIPR agonists SP-2991 (PO, 30 mg/kg) Semaglutide (SC, 10 nmol/kg) Dual-GIPR / GCGR agonists 80 ~24% Semaglutide (SC, 10 nmol/kg) Vehicle (PO) Triple-GLP-1R / GIPR / GCGR agonists p < 0.005
Tirzepatide (SC, 10 nmol/kg) 70 Vehicle (PO) ~33% 60 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Days 2025 SEPTERNA 22 Body Weight (%)
Building a World-Class GPCR-Focused Biotechnology Company 2025
Proven Leaders in GPCR Drug Development and Company Building Senior
Leadership Jeff Finer, MD PhD Liz Bhatt, MS MBA Jae Kim, MD Gil Labrucherie, CFA JD Uwe Klein, PhD Dan Long, DPhil Samira Shaikhly CEO COO CMO CFO SVP Biological Sciences SVP Drug Discovery CPO Board of Directors Academic Co-Founders Jeff