Slide 1: Developing Innovative Medicines to Treat Obesity and Other Metabolic Diseases
Developing Innovative skye’ Medicines to Treat Obesity and Other Metabolic Diseases May 2025 (_ Nasdaq: SKYE) (_ Nasdaq: SKYE) A ee...
Slide 2: Disclaimer and Important Information for Investors
Disclaimer and Important Information for Investors This presentation (“Presentation”) has been prepared solely for general information purposes by or on behalf of Skye Bioscience, Inc. (together with its subsidiaries and affiliates, “Skye”). This Presentation is for informational purposes only and i
Slide 3: Mission
Mission Pioneer and commercialize the first CB1 antibody to tackle current and future unmet needs of obesity GLP-1s GLP-1 Drugs in Development All drugs are investigational and subject to regulatory approval. OPPORTUNITY The GLP-1 space is incredibly crowded with multiple marketed and soon-to-be-app
Slide 4: Significant Opportunity Remains in Anti-Obesity Drug Market
Significant Opportunity Remains in Anti-Obesity Drug Market GLP-1RA have issues with tolerability and lean mass loss Opportunity Gastrointestinal Wegovy® and Zepbound® cause significant rates of nausea Improved Issues (31-53%), diarrhea (23-35%) and vomiting (12-30%) tolerability Blue Health Intelli
Slide 5: Pattern of GLP-1 Discontinuation
Pattern of GLP-1 Discontinuation Most adults with overweight or obesity discontinue GLP-1 RA therapy within one year Discontinuation and Reinitiation Rates Strongly Correlated with GI Intolerability Time to Primary Discontinuation of GLP-1 RA Therapy Nearly 2/3rds of patients discontinue after 1 yea
Slide 6: CB1: Overlooked Non-incretin Strategy to Tackle Weight Loss
CB1: Overlooked Non-incretin Strategy to Tackle Weight Loss Non-incretins target peripheral receptors and generally do not have central activity Non-incretin-based Approach: Opportunity for healthier, Incretin-based Approaches, Using sustainable weight loss Food-intake and Blood-sugar Current target
Slide 7: CB1 Inhibition Can Result in Meaningful Weight Loss, as Demonstrated by Rimonabant and Monlunabant
CB1 Inhibition Can Result in Meaningful Weight Loss, as Demonstrated by Rimonabant and Monlunabant 16-Week Placebo- GI Tolerability Adjusted Weight Loss All drugs are investigational and subject to regulatory approval. Monlunabant1,2 ~6% ~30% Rimonabant3 ~3% ~30% However, monlunabant’s Oral Semaglut
Slide 8: Nimacimab Target Product Profile
Nimacimab Target Product Profile Opportunity across multiple treatment settings Monotherapy Maintenance Combination Patients with high BMI or who Addressable Patients who are contraindicated, intolerant, and/or unresponsive require additional weight loss All drugs are investigational and subject to
Slide 9: Targeting CB1 – Broad Metabolic Potential with Clinically Validated Mechanism of Action
Targeting CB1 – Broad Metabolic Potential with Clinically Validated Mechanism of Action
Slide 10: Nimacimab: First-in-Class, Peripherally-restricted CB1-inhibiting Antibody
Nimacimab: First-in-Class, Peripherally-restricted CB1-inhibiting Antibody • Stable antibody with half-life of 18-21 days (potential bi-weekly or monthly dosing) Engineered IgG4 • Single mutation in the hinge region that prevents antibody Fab exchange All drugs are investigational and subject to reg
Slide 11: Peripheral CB1 Signaling: Metabolic-focused Target
Peripheral CB1 Signaling: Metabolic-focused Target CB1 engagement promotes inflammatory, fibrotic and metabolic diseases in various organs with significant prevalence; blocking CB1 can reverse negatively-trending pathologies CB1 Nimacimab Key Differentiators All drugs are investigational and subject
Slide 12: Superior Exclusion of CB1 Inhibitor from Brain; No Neuropsychiatric Side Effects
Superior Exclusion of CB1 Inhibitor from Brain; No Neuropsychiatric Side Effects NHP and Ph1 data highlight nimacimab’s lack of CNS accumulation Day 1 Day 8 Day 15 Phase 1 data showed absence of Cyno (post 1st dose) (post 2nd dose) (post 3rd dose) negative neuropsychiatric CSF/Serum BLQ <0.02% <0.02
Slide 13: Favorable Comparison of Nimacimab and Semaglutide in Diet-Induced Obesity Model
Favorable Comparison of Nimacimab and Semaglutide in Diet-Induced Obesity Model Nimacimab shows dose-dependent weight loss, reduced fat mass, and lean mass preservation Body Composition All drugs are investigational and subject to regulatory approval. Q3D Q3D Body weight and composition analyses per
Slide 14: Productive Modulation of Key Hormones with Nimacimab Treatment
Productive Modulation of Key Hormones with Nimacimab Treatment Ghrelin GLP-1 Leptin Resistin All drugs are investigational and subject to regulatory approval. Serum was collected on day 36 and hormone levels were determined with a Bio Plex multi-Plex immunoassay. For all analyses: one-way ANOVA repe
Slide 15: Dose-dependent Improvement in Glycemic Control
Dose-dependent Improvement in Glycemic Control Fasting Insulin Glucose Tolerance Test GTT (AUC) 30000 Blood Glucose (mg/dL) Glucose AUC (mM/120min) All drugs are investigational and subject to regulatory approval. 20000 10000 Q3D GTT analyses: 2-way ANOVA repeated measurements (Tukey multiple compar
Slide 16: Nimacimab Treatment leads to Broad Metabolic Improvements
Nimacimab Treatment leads to Broad Metabolic Improvements Dose-dependent reduction in inflammation and steatosis Inflammatory Analysis of White Adipose Tissue Liver Steatosis Analysis F4/80 Steatosis Score Steatosis Percent Area (macrophage) 3 # **** All drugs are investigational and subject to regu
Slide 17: Comparable Results: Repeat DIO Study in 2nd Independent Lab
Comparable Results: Repeat DIO Study in 2nd Independent Lab Independent repeat of weight loss with lean mass preservation + reduced fat mass Body Composition All drugs are investigational and subject to regulatory approval. Body weight and composition analyses performed with two-way ANOVA repeated m
Slide 18: Nimacimab Led to Reduced Food Intake
Nimacimab Led to Reduced Food Intake Reduced caloric intake with nimacimab comparable to semaglutide Cumulative Food Intake Caloric Intake vs Body Weight 20 Change in slope on treament Semaglutide = +7% Nimacimab = -53% Average Daily Energy Intake 15 All drugs are investigational and subject to regu
Slide 19: Glycemic Control with Nimacimab Consistent w/ Previous Study
Glycemic Control with Nimacimab Consistent w/ Previous Study Semaglutide and nimacimab improved glycemic control in obese mice Glucose Tolerance Test Glucose AUC All drugs are investigational and subject to regulatory approval. Day 27 mice were fasted for 4h before ip injection of 10g glucose GTT an
Slide 20: Potential for Combination with Tirzepatide
Potential for Combination with Tirzepatide Improved weight loss and body composition in diet-induced obesity model using clinically translatable dosing of nimacimab All drugs, except tirzepatide marketed by Lilly, are investigational and subject to regulatory approval. Body Composition QD Q3D Nimaci
Slide 21: Nimacimab Potency Similar to Small Molecule Inhibitors
Nimacimab Potency Similar to Small Molecule Inhibitors Based on both cAMP and -arrestin assays cAMP-based Assay -Arrestin-based Assay All drugs are investigational and subject to regulatory approval. CB1 Inhibitor IC50 (nM) CB1 Inhibitor IC50 (nM) Nimacimab 4.96 Nimacimab 10.83 AM6545 (neutral ant
Slide 22: Non-competitive CB1 Inhibition: Differentiation of Nimacimab's Allosteric Modulation
Non-competitive CB1 Inhibition: Differentiation of Nimacimab’s Allosteric Modulation Monlunabant Nimacimab 2-AG or AEA 2-AG or AEA Monlunabant Nimacimab non- competes with competitively binds AEA/2-AG for allosteric site; binding to the AEA/2-AG binds the orthosteric site orthosteric site All drugs
Slide 23: Nimacimab Restores Metabolic Homeostasis
Nimacimab Restores Metabolic Homeostasis CB1 inhibition results in coordinated metabolic changes in multiple tissues Adipose Tissue Liver and Pancreas GI Tract Muscle All drugs are investigational and subject to regulatory approval. Leptin Fibrosis Ghrelin Insulin Sensitivity Resistin Steatosis GLP-
Slide 24: Complementary, Not Competitive
Complementary, Not Competitive CB1 impacts key metabolic pathways that complement existing products & strategies KEY TARGETS / MECHANISMS Opportunities for Key Targets GLP-11 GIP1 Glucagon1 Amylin2-4 Myostatin5-7 CB18-9 Nimacimab Characteristics Decreases Appetite / ✓ ? (limited) x ✓ x ✓ ✓ Magnitude
Slide 25: Nimacimab's Differentiation
Nimacimab’s Differentiation Differentiated Receptor Superior Exclusion Clinical and Preclinical Engagement from the Brain Validation All drugs are investigational and subject to regulatory approval. Allosteric modulation leads to As an antibody, nimacimab has CB1 inhibition for weight loss non-compe
Slide 26: Clinical & Regulatory
skye Clinical & Regulatory CBeyérid’ A ee .2.
Slide 27: Phase 2a CBeyond Trial: Patients with Overweight or Obesity
Phase 2a CBeyondTM Trial: Patients with Overweight or Obesity Enrollment completed for initial 26-week treatment period Primary Endpoint: Randomization Monotherapy 2:2:1:1 Nimacimab 200 mg QW* Double-blinded (N=40) Placebo-matching Nimacimab 200 mg QW (N=40) Screening All drugs are investigational a
Slide 28: Nimacimab and Adverse Events of Interest
Nimacimab and Adverse Events of Interest • AESIs associated with CB1 inhibitors are concerned with neuropsychiatric and neurological effects • Skye has included multiple questionnaires and tests to evaluate the frequency of AESIs, which are provided to and reviewed by the DSMC Columbia-Suicide Sever
Slide 29: CBeyond Phase 2 Study Extension
CBeyondTM Phase 2 Study Extension Continuing Combination Arms (52 Weeks) Monotherapy Arms (~July 2025) Up to 4 13 Week Eligible for Eligible for 26 Week 26 Week Weeks Follow-up Study Study Treatment Treatment from Last period Extension Extension Dose All drugs are investigational and subject to regu
Slide 30: Clinical and Regulatory Milestones
Clinical and Regulatory Milestones 2025 2026 2027 All drugs are investigational and subject to regulatory approval. H2 Q4 H1 Q2 Q3 Q4 Q2 Phase 3 CBeyondTM EOP-2 CBeyond Initiate CMC P3 Complete Phase 2b Phase 2a meeting extension top- Phase 2b validations Phase 2b top-line top-line line data (CBeyon
Slide 31: Well-positioned to Become Fully Integrated Metabolic Company
Well-positioned to Become Fully Integrated Metabolic Company Experienced in therapeutic drug regulatory process through approval and commercialization Robust IP, Life-Cycle and 1 Development Strategy Planned nimacimab EOP2 by 2027 and IP/composition of matter protection through 2035* Team and collab
Slide 32: Select Financial Figures & Metrics
Select Financial Figures & Metrics Stock Information • $107M in equity capital raised since Listed: Nasdaq • SKYE August 2023 Stock Price1 • $1.79 • Supported by top-tier specialist life All drugs are investigational and subject to regulatory approval. science investors Shares Outstanding2 • 31.0M •
Slide 33: Leadership
Contributed to commercialization of 40+ drugs/diagnostics, led high-value Leadership strategic transactions, and co-founded multiple companies Executive Management Board of Directors Punit Dhillon Kaitlyn Arsenault, CPA Tu Diep, MSc Paul Grayson Annalisa Jenkins, Deborah Charych, PhD President & CEO
Slide 34: Please learn more or contact us
11250 El Camino Real, Suite 100 San Diego, CA 92130 Please learn more or contact us at: ir@skyebioscience.com +1 (858) 410-0266 © 2025 Skye Bioscience, Inc.
Slide 35: Obesity Disease Overview
Obesity Disease Overview Obesity is a chronic disease characterized by excessive body fat and adipose tissue inflammation, driven by a complex and multifactorial etiology Pathophysiology • Energy Imbalance: Obesity results from chronic positive energy balance due to energy intake greater than energy
Slide 36: Obesity U.S. Patient Population
Obesity U.S. Prevalence of obesity among U.S. adults is expected to reach Patient Population ~141 M by 2035, outpacing general U.S. population growth U.S. Adult Prevalence of Obese Individuals Obesity Population Dynamics Class I Class II Class III • Prevalence: Obesity prevalent in ~119 M patients i
Slide 37: Obesity Comorbidities
Obesity Comorbidities Obesity associated with significant comorbidities, ie. diabetes, hypertension, and kidney disease • Obesity is a whole-body condition that affects numerous organ systems including the cardiovascular, respiratory, endocrine, neurologic, and musculoskeletal systems, among others
Slide 38: U.S. Obesity Clinical-stage Competitive Pipeline
U.S. Obesity Clinical-stage Competitive Pipeline U.S. obesity market faces intense/increasing competition: 5 Phase 3, 36 Phase 2, and 29 Phase 1 programs are primarily focused on GLP-1s; only 3 CB1 assets in clinical development Unique Competitors in the U.S. Obesity Clinical Pipeline Key Pipeline I