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Amylin Development Candidate ACCG-2671 December 17, 2024
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2 Forward looking statements This presentation contains “forward-looking statements” within the meaning of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995. All statements other than statements of historical fact are statements that could be deemed forward-looking statements, including, without limitation, statements concerning the Company's future plans and prospects; any expectations regarding the safety, efficacy, tolerability, scalability and combinability of ACCG-2671, GSBR‐1290 and other candidates under development, the ability of ACCG-2671 and GSBR‐1290 to treat obesity, T2DM, or related indications; the potential market opportunities; the timing and clinical strategy for ACCG-2671; the ability of the Company to expand to additional indications; and the planned timing of the Company's anticipated milestones and data results for its various programs. In addition, when or if used in this presentation, the words “may,” “could,” “should,” “anticipate,” “believe,” “estimate,” “expect,” “intend,” “plan,” “predict” and similar expressions and their variants, as they relate to the Company may identify forward-looking statements. Forward-looking statements are neither historical facts nor assurances of future performance. Although the Company believes the expectations reflected in such forward-looking statements are reasonable, the Company can give no assurance that such expectations will prove to be correct. Readers are cautioned that actual results, levels of activity, safety, performance or events and circumstances could differ materially from those expressed or implied in the Company’s forward-looking statements due to a variety of risks and uncertainties, which include, without limitation, risks and uncertainties related to the preliminary nature of the results due to length of the study and sample size and results from earlier clinical studies not necessarily being predictive of future results, potential delays in the commencement, enrollment and completion of the Company’s planned and current clinical and current studies, the Company’s ability to advance GSBR-1290, LTSE-2578, ANPA-0073, ACCG-2671 and its other therapeutic candidates, obtain regulatory approval of and ultimately commercialize the Company’s therapeutic candidates, competitive products or approaches limiting the commercial value of the Company’s product candidates, the timing and results of preclinical and clinical studies, the Company’s ability to fund development activities and achieve development goals, the Company's reliance on third parties, including clinical research organizations , manufacturers, suppliers and collaborators, over which it may not always have full control, the impact of any global pandemics, inflation, supply chain issues, rising interest rates, future bank failures and other macroeconomic factors on the Company’s business, its ability to protect its intellectual property and other risks and uncertainties described in the Company’s filings with the Securities and Exchange Commission (SEC), including the Company’s Annual Report on Form 10-K for the year ended December 31, 2023 filed with the SEC on March 8, 2024, Quarterly Report on Form 10-Q for the quarter ended September 30, 2024 filed with the SEC on November 13, 2024, and future reports the Company may file with the SEC from time to time. All forward-looking statements contained in this presentation speak only as of the date on which they were made and are based on management’s assumptions and estimates as of such date. 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, except as required by law.
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3 Agenda Opening Remarks • Technology Platform and Discovery of Small Molecule Amylin Receptor Agonist Raymond Stevens, Ph.D. Chief Executive Officer Amylin Receptor Agonist Program • Amylin Biology • ACCG-2671 Development Candidate Profile Fang Zhang, Ph.D. EVP , Head of Biology Building a Leading Oral Small Molecule Portfolio • Combination therapy approach Raymond Stevens, Ph.D. CEO Q&A Raymond Stevens, Ph.D., CEO Blai Coll, M.D., Ph.D., CMO Xichen Lin, Ph.D., CSO Fang Zhang, Ph.D., EVP , Head of Biology Jun Yoon, CFO Confidential
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4 Mission: Bring Small Molecule Innovation to Areas of Great Unmet Need Amylin Receptor Agonist PEPTIDE MEDICINES ACCESSIBLE FOR ALL Amylin Receptor Agonist SMALL MOLECULE Oral Small Molecule Opportunities • Broader accessibility • Oral formulation provides more patient options • Potential for long-term weight loss maintenance • Large-scale manufacturing; lower cost of goods • Potential fixed dose combination advantages Confidential
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5 Disrupting the GLP-1R Peptide-Dominated Market with Oral Small Molecules 2005/2010 2014 2017 2019 2021 2022 GLP-1R GLP-1R/GIPR Peptide Drugs on the Market Incretin drugs evolution – Aimed at improving convenience & efficacy for patients Approval: Our powerful platform enables a franchise approach to potentially complement and replace the marketed peptides GLP-1R + Amylin GLP-1R + Incretin Amylin + Incretin CombinationGLP-1R GSBR-1290 Phase 2b GLP-1R/GIPR GLP-1R/GCGR GLP-1R/GIPR/GCGR Dual, Triple Agonist Molecule Hit Identification Our Small Molecule Incretin Franchise Amylin ACCG - 2671 Development Candidate Confidential
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6 Cutting Edge Computational + Technology Platform GPCR conformation dynamics Binding site sidechain dynamics Proprietary cryo-EM workflow captures GPCR dynamics Simulated conformations using molecular dynamics INTEGRATION Ligand binding pose dynamics Validated Targets (GPCR + Peptide) Integrating GPCR Dynamics for Structure-Based Drug Design • Intrinsic dynamic conformations provide additional structure-function insight • Ligand binding site flexibility enables molecule design for novel and differentiated properties • Induced-fit ligand binding dynamics significantly advances structure enablement leading to accelerated hit and lead discovery Confidential
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7 ACCG-2671: Oral Small Molecule Amylin Receptor Agonist Target Product Profile Competitive Efficacy Comparable preclinical efficacy to cagrilintide – a dual amylin calcitonin receptor agonist (DACRA) peptide Safety Suitable for chronic disease treatment Pharmacokinetics Predicted once daily oral dosing Scalability Manufacturable and scalable at low COGS Combinability Combinable with small molecule GLP-1RA and other incretins Confidential
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8 Amylin Receptor Agonist Program Amylin Biology ACCG-2671 Development Candidate Profile Confidential
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9 ✓ Reduce appetite ✓ Increase satiety Brain ✓ Reduce appetite ✓ Increase satiety ✓ Increase leptin sensitivity ✓ Increase energy expenditure ✓ Slow gastric emptying Stomach ✓ Slow gastric emptying ✓ Stimulate insulin secretion ✓ Inhibit glucagon secretion Pancreas ✓ Inhibit glucagon secretion ✓ Improve insulin sensitivity ✓ Reduce fat accumulation Liver ✓ Improve insulin sensitivity ✓ Reduce fat accumulation ✓ Reduce fat and related inflammation White Adipose tissue ✓ Reduce fat and related inflammation Muscle tissue ✓ Preserve lean mass GLP-1 Secreted from L-cells of the small intestine Amylin Co-secreted with insulin from pancreatic beta cells References: 1. Mathiesen et al. Eur J Endocrinol 2022;186(6):R93–R111 2. Hey et al. Pharmacol Rev. 2015;67(3):564-600 3. Roth JD, et al. Int J Obes (Lond). 2008;32(8):1201-1210. 4. Mack C, et al. Am J Physiol Regul Integr Comp Physiol. 2007;293(5):R1855 -R1863 Multiple Potential Beneficial Physiological Effects of Amylin and GLP-1 5. Melson, E., et al. Int J Obes (2024). 6. Baggio LL, Mol Metab. 2021;46:101090. 7.Wilding JPH, et al. N Engl J Med. 2021;384(11):989-1002.
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10 Complexity of the Amylin Receptor Signaling Pathway: DACRA & SARA Profiles AMYLIN RECEPTOR (AMY3R) (CTR + RAMP3) CALCITONIN RECEPTOR (CTR) AMY1R, AMY2R SARA (Selective Amylin Receptor Agonist) DACRA (Dual Amylin & Calcitonin Receptor Agonist) AMY3 Selective Peptide AMY3 Selective Small Molecule DACRA Peptide DACRA Small Molecule -Arrestin -Arrestin Gs + other signaling pathways Gs + other signaling pathways Evidence for ligand-dependent and independent equilibration of RAMP bound forms of CTR based on Gostynska et. al 2024. https://www.biorxiv.org/content/10.1101/2024.10.09.617487v1 G-proteins activated for CTR.AMYRs based on: Fletcher (2021) doi:10.1124/jpet.121.000567 Amylin Receptor Complex Calcitonin Receptor Complex Amylin Receptor Complex Gs + other signaling pathways -Arrestin -Arrestin Gs + other signaling pathways Confidential
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11 Evidence for ligand-dependent and independent equilibration of RAMP bound forms of CTR based on Gostynska et. al 2024. https://www.biorxiv.org/content/10.1101/2024.10.09.617487v1 Our Structure-Based Drug Discovery Approach to Generate Multiple Small Molecule Candidates for Optimal Therapeutic Benefit Multiple Small Molecule Candidates CTR DACRA Small Molecule CTR DACRA Peptide AMY3R DACRA Peptide AMY3R DACRA Small Molecule Cryo-EM structures of small molecule/ peptide bound AMY3R/CTR Structure Based Drug DiscoveryAgonist SARA (Selective Amylin Receptor Agonist) DACRA (Dual Amylin and Calcitonin Receptor Agonist) AMYLIN RECEPTOR (AMY3R) (CTR + RAMP3) CALCITONIN RECEPTOR (CTR) AMY1R, AMY2R Partnership FEP – free energy perturbation ML – machine learning Amy3R pEC50 FEP predicted pEC50 values Predictive FEP+ and ML models led to ACCG-2671
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Confidential 12 ACCG-2671 Preclinical Results Support Development Candidate Selection Injectable Peptide Oral Small Molecule Cagrilintide ACCG-2671 In vitro affinity Ki hAMY3R 3.5 nM <5 nM Ki hCTR 6.8 nM <5 nM In vivo efficacy Body Weight Loss (DIO rats) 11.4% @7.5nmol/kg s.c. QD 14.8% @15 mpk p.o. QD Preclinical Safety In vivo N/A Tolerability up to 300 mpk in rat dose range finding In vitro N/A hERG (>100x) GSH Negative Human Dose Dose & Frequency 2.4 mg s.c. / QW Predicted <100 mg / QD ACCG-2671 Development Candidate Profile • Dual Amylin and Calcitonin Receptor Agonist (DACRA) • Nanomolar in vitro binding affinity to amylin and calcitonin receptors • Sub-nanomolar in vitro functional activity on amylin and calcitonin receptors • In vivo efficacy comparable to cagrilintide DACRA in Diet-Induced Obesity (DIO) models • Robust efficacy in combination treatment with semaglutide in DIO models • Preclinical safety profile supports development candidate selection • Preclinical PK supports once-daily oral dosing in human Note: The in-house data included here are based on preclinical studies conducted by the Company except for human dose. In vivo efficacy data are based on separate preclinical DIO studies of cagrilintide and ACCG-2671 GSH: Glutathione trapping liver microsomes assay; hERG: human ether-a-go-go-related gene potassium channel Confidential
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13 ACCG-2671 Demonstrates Sub-nanomolar Potency of DACRA Activity In Vitro Binding Affinity In Vitro Functional Activity • Nanomolar in vitro binding affinity to amylin and calcitonin receptors • Sub-nanomolar functional activity and balanced selectivity to amylin and calcitonin receptors * in vitro potency determined using cAMP induction assays in cell lines overexpressing the indicated receptor. Data are presented as mean ± standard deviation (SD). cAMP Induction* -15 -14 -13 -12 -11 -10 -9 -8 -7 -6 -20 0 20 40 60 80 100 120 Log [Agonist], M Relative activity, % Cagrilintide, hAMY3R Cagrilintide, hCTR ACCG-2671, hAMY3R ACCG-2671, hCTRAmylin Receptor hAMY3R (Ki, nM) Calcitonin Receptor hCTR (Ki, nM) Calcitonin 14.6 1.1 Amylin 0.6 14.8 Cagrilintide 3.5 6.8 ACCG-2671 < 5 < 5 hCTR: human calcitonin receptor; hAMY3R: human amylin 3 receptor; Ki: inhibitory constant Calcitonin: human calcitonin; Amylin: rat amylin
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14 ACCG-2671 Achieves Cagrilintide-like Efficacy in Preclinical DIO Rat Model Acute Food Intake Reduction 0 5 10 15 20 25 Food intake (g) for 24h **** 0 5 10 15 20 25 Food intake (g) for 24h ** ******** Vehicle Vehicle 0.15 mpk 1.5 mpk 15 mpk Cagrilintide ACCG-2671 Chronic Body Weight Loss Cagrilintide ACCG-2671 -20 -15 -10 -5 0 5 10 Body weight change (%) Day 28 ** **** -20 -15 -10 -5 0 5 10 Body weight change (%) Day 23 **** ** Vehicle 0.15 mpk 1.5 mpk 15 mpk Single oral administration Repeated oral administration *p<0.05, **p<0.01, ***p<0.001,****p<0.0001 vs Vehicle group by one-way ANOVA test. Cagrilintide treatment study, N = 6 per group; ACCG-2671 treatment study, N = 7 per group • ACCG-2671 dose dependently reduced food intake in DIO rats • ACCG-2671 oral daily dosing for 28 days significantly reduced body weight in DIO rats Vehicle 0.25 nmol/kg 0.75 nmol/kg 7.5 nmol/kg 0.25 nmol/kg 0.75 nmol/kg 7.5 nmol/kg Single s.c. administration Repeated s.c. administration Note: The in-house data included here is based on a preclinical comparison study of cagrilintide and ACCG-2671 by Company.
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15 Our Oral Small Molecule Amylin Development Candidate ACCG-2671: Cagrilintide-like efficacy with oral small molecule profile VALIDATED BIOLOGY • Promotes satiety to enhance feelings of fullness, reducing food intake • Slows gastric emptying to delay digestion and absorption for longer periods of satiety • Reduces body weight with selective fat loss: Increases energy expenditure, with lean mass preservation • Potential improved tolerability over GLP-1RA monotherapy • Pathway validated by cagrilintide and CagriSema in multiple late-stage clinical trials PRECLINICAL PROFILE • Potent and balanced in vitro activities of cAMP induction on AMY3R and CTR • Robust in vivo efficacy in preclinical models with mono- and combination therapy • PK supports once-daily oral dosing in human • Safety profile supports chronic treatment Most Advanced Small Molecule* *ACCG-2671 is the first oral small molecule amylin-based development candidate declared. ACCG - 2671 (Oral Amylin)
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16 ACCG-2671 Clinical Development Strategy Q4 2024 1H 2025 2H 2025 1H 2026 2H 2026 ❑ Phase 1 SAD/MAD Start by YE 2025 ✓ First Development Candidate Q4 2024 ❑ IND-Enabling Studies ❑ 1 mo and 3 mo GLP-Tox Studies ❑ Phase 1 SAD/MAD Data YE 2026 NEXT STEPS • Initiated GMP manufacturing to support GLP-Tox and early clinical development • Longer term tox studies to enable Phase 2 studies • Phase 1 SAD/MAD to initiate by year-end 2025 • Phase 2 plans include monotherapy and combination studies with GLP-1RA for chronic weight management ❑ Additional Development Candidates *ACCG-2671 is the first oral small molecule amylin-based development candidate declared. Most Advanced Small Molecule* ACCG - 2671 (Oral Amylin)
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17 Building a Leading Oral Small Molecule Portfolio Combination therapy approach Confidential
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18 Phase 2 program underway Top-line data expected in Q4 2025 Development Candidate selected Phase 1 initiation expected by YE 2025 GLP-1R (GSBR-1290) Amylin (ACCG-2671) Two Oral Small Molecule Backbone Mechanisms for the Obesity Market and Beyond • Oral small molecule; once-daily dosing • Monotherapy backbone for chronic maintenance with potential best-in- class efficacy and safety • Potential fixed-dose combination with other oral non-peptides • Oral small molecule; once-daily dosing • Potential for tolerability advantages • Lean muscle mass preservation potential • Potential fixed-dose combination with other oral non-peptides • Potential for greater body weight loss and enhanced tolerability • Potential broader label expansion into additional clinical indications GLP-1R + Amylin All Oral Combination
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19 Metabolic Franchise Strategy – Combinations and Potential Indication Expansion Osteo- arthritis MASH Obesity CKD Parkinson’s/ Alzheimer’s Heart Failure Sleep Apnea Other Incretins and Hormones Selective Weight Loss Addiction Combinations Therapeutic Area POTENTIAL INDICATION OPPORTUNITIES ORAL SMALL MOLECULE METABOLIC FRANCHISE Oral GLP-1 GSBR-1290 GCG Receptor GIP Receptor APJ Receptor Type 2 Diabetes Oral Amylin ACCG-2671 Combination Backbones
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20 Strong YE 2024 Finish Going into 2025 Milestones 2024 GSBR-1290 Phase 2a Obesity Data (12 week) ✓ IND cleared for chronic weight management ✓ Phase 2b ACCESS and ACCESS II Initiation (36 week) ✓ ACCG-2671 Nominated ACCG-2671 as First Amylin Agonist Development Candidate ✓ ANPA-0073 Initiated 6/9-month GLP-Tox studies ✓ LTSE-2578 Initiated Phase 1 SAD/MAD study ✓ Financing Raised $547 million Follow On Financing ✓
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21 GSBR-1290 (Oral GLP-1R) ✓Phase 2b ACCESS/ACCESS II Start ✓ Phase 2a Data ❑ ACCESS/ACCESS II Data Q4 2025 Oral GIPR Anticipated Milestones – Entire Small Molecule Portfolio ANPA-0073 (Oral APJR) Phase 2 Ready ✓ Selective Weight Loss Preclinical Validation Obesity ACCG-2671 (Oral AmylinR) Oral GCGR ❑ Phase 3 Start 2026 ❑Phase 1 Start YE 2025 ✓ Development Candidate ❑ Phase 1 Data YE 2026 ❑Phase 1 Start 2026 ❑ Development Candidate 2025 ❑ Development Candidate 2026 Lead Optimization Lead Optimization Lead OptimizationHits Hits Hits Discovery ❑ Selective Weight Loss Clinical Study 1H 2024 1H 2025 2H 20252H 2024 2026 LTSE-2578 (Oral LPA1R) ❑ Phase 1 Data 2025 ✓ Phase 1 Start SAD/MAD2 1. Cash includes cash, cash equivalents and short-term investments 2. Single-ascending dose/Multiple-ascending dose (SAD/MAD) Robust Portfolio and Multiple Expected Catalysts ~$915.3 M cash1 as of September 30, 2024
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22 Thank you ir@structuretx.com www.structuretx.com