Slide 1: Developing Innovative Medicines to Treat Obesity and Other Metabolic Diseases
Developing Innovative skye’ Medicines to Treat Obesity and Other Metabolic Diseases July 2025 (_ 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 Time to Primary Discontinuation of GLP-1 RA Therapy Discontinuation and Reinitiation Rates Strongly Correlated with GI Intolerability Nearly 2/3rds of patients discontinue after 1 yea
Slide 6: CB1: Overlooked Non-incretin Target to Tackle Weight Loss
CB1: Overlooked Non-incretin Target 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 targets:
Slide 7: CB1 Inhibition Can Result in Meaningful Weight Loss
CB1 Inhibition Can Result in Meaningful Weight Loss, as Demonstrated by Rimonabant and Monlunabant 16-Week Placebo- GI Tolerability Adjusted Weight Loss Monlunabant1,2 ~6% ~30% All drugs are investigational and subject to regulatory approval. Rimonabant3 ~3% ~30% Oral Semaglutide4 ~5% ~80% (50 mg) S
Slide 8: Nimacimab is Differentiated from the Small Molecule CB1 Inhibitors
Nimacimab is Differentiated from the Small Molecule CB1 Inhibitors Peripheral Restriction Negative Allosteric Modulator 2-AG or AEA All drugs are investigational and subject to regulatory approval. Significantly less brain Unlike small molecules, penetration than small nimacimab retains potency even
Slide 9: Four Mechanistic Pillars of Nimacimab
Four Mechanistic Pillars of Nimacimab 01 02 03 04 Peripheral Modulation Improvement Enhanced Lipid Reduction of Obesity- of Appetite Regulating and Restoration of Metabolism Induced Inflammation Hormones Glycemic Control All drugs are investigational and subject to regulatory approval. Leptin Resist
Slide 10: Monlunabant – What's Novo Saying and Doing
Monlunabant – What’s Novo Saying and Doing Confidence in weight-loss potential of CB1, but knowledge that CNS exposure must be minimized to reduce neuropsychiatric concerns “The phase 2a results indicate the Ongoing Clinical Research: weight-lowering potential of Phase 1 Completed: A Research Study
Slide 11: An Overcrowded GLP-1 Space
An Overcrowded GLP-1 Space Nausea Rates (%) 0 10 20 30 40 50 60 70 80 90 100 0 Where Nimacimab -5 Fits GSBR-1290 (12w) HRS-7535 (36w) All drugs are investigational and subject to regulatory approval. -10 Percent Weight Loss Monotherapy (Placebo-Adjusted) Maintenance Semaglutide (68w) Orforglipron (3
Slide 12: Why Nimacimab: The Future of Metabolic Tx
Why Nimacimab: The Future of Metabolic Tx Nimacimab clinical and preclinical differentiation Established to Date Looking Ahead to the Rest of 2025 Durable weight loss and restoration of metabolic homeostasis Nimacimab reduces fat mass but preserves lean mass and modulates key hormones (↑ GLP1, ↓ lep
Slide 13: Targeting CB1 – Broad Metabolic Potential with Clinically Validated Mechanism of Action
Targeting CB1 – Broad Metabolic Potential with Clinically Validated Mechanism of Action
Slide 14: Peripheral CB1 Signaling: Metabolic-focused Targets
Peripheral CB1 Signaling: Metabolic-focused Targets Active CB1 engagement promotes inflammation, fibrosis, and metabolic dysfunction; blocking peripheral CB1 can reverse negatively-trending pathologies CB1 All drugs are investigational and subject to regulatory approval. Liver & Digestive Adipose Ti
Slide 15: Nimacimab: Peripherally-restricted CB1-inhibiting Antibody
Nimacimab: Peripherally-restricted CB1-inhibiting Antibody • Stable antibody with half-life of 18-21 days (potential bi-weekly or monthly dosing) Long Half-life • Single mutation in the hinge region that prevents antibody Fab exchange • Multiple NHP studies: background levels in CNS/brain (even at h
Slide 16: 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 17: Nimacimab Achieves Peripheral CB1 Inhibition Without CNS Risk
Nimacimab Achieves Peripheral CB1 Inhibition Without CNS Risk Superior peripheral restriction vs. small molecules: over 750% of IC₉₀ in periphery, with <1% CNS exposure Rimonabant: • 5mg and 20mg doses have significant brain exposure, resulting in neuropsychiatric effects at both doses. • Only 20mg
Slide 18: 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 19: 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 20: Repeat DIO Study with Independent Lab
Repeat DIO Study with Independent Lab: Similar Weight Loss with Reduced Fat Mass Body Weight Body Composition All drugs are investigational and subject to regulatory approval. Body weight and composition analyses were performed with two-way ANOVA repeated measurements. Tukey multiple comparison test
Slide 21: Nimacimab Led to Reduced Food Intake
Nimacimab Led to Reduced Food Intake Reduced caloric intake with nimacimab comparable to semaglutide – supporting centrally mediated appetite suppression without CNS penetration Cumulative Food Intake Caloric Intake vs Body Weight All drugs are investigational and subject to regulatory approval. Mix
Slide 22: Productive Modulation of Key Hormones with Nimacimab
Productive Modulation of Key Hormones with Nimacimab Peripheral CB1 inhibition modulates gut and adipose tissue hormones important for central control of appetite GLP-1 Leptin Resistin All drugs are investigational and subject to regulatory approval. Serum was collected on day 36 and hormone levels
Slide 23: Nimacimab Improves Glycemic Control
Nimacimab Improves Glycemic Control All drugs are investigational and subject to regulatory approval. 24 Day 27 mice were fasted for 4h before collecting serum to measure glucose and insulin levels. Day 27 mice were fasted for 4h before ip injection of 2g/kg glucose. GTT © 2025 Skye analyses: Biosci
Slide 24: Nimacimab Treatment Promotes Lipid Metabolism
Nimacimab Treatment Promotes Lipid Metabolism Dose-dependent reduction in steatosis and serum cholesterol Steatosis Analysis (Liver) Serum Steatosis Score Steatosis Percent Area Cholesterol All drugs are investigational and subject to regulatory approval. Control Diet Vehicle Nimacimab 24 mg/kg Nima
Slide 25: Nimacimab Improves Obesity-related Inflammation
Nimacimab Improves Obesity-related Inflammation Reduced Inflammation, Fibrosis, and Adipocyte Area Serum Inflammation Markers Fibrosis Area Macrophage (F4/80) Density Cytokine Array Liver All drugs are investigational and subject to regulatory approval. Adipocyte Area Macrophage (F4/80) Density iWAT
Slide 26: Study Design: Nima/TRZ/Combo with Rebound/Maintenance
Study Design: Nima/TRZ/Combo with Rebound/Maintenance Phase A: Monotherapy and Phase B: Asses Rebound or 8 weeks Combo with Sub-optimal TRZ Maintenance with Nimacimab Tissue Days -7 24 2 45 collection male hCB1 5 MRI MRI MRI N=8 16 weeks on HFD Vehicle Vehicle HFD All drugs are investigational and s
Slide 27: Nimacimab Enhances Weight Loss When Combined with Low-Dose Tirzepatide
Nimacimab Enhances Weight Loss When Combined with Low-Dose Tirzepatide Absolute Weight Vehicle-adjusted % Weight Loss The daily average change in body weight from day 1 of treatment from the vehicle group was subtracted from the individual change in body All drugs are investigational and subject to
Slide 28: Nimacimab Maintains Post-Treatment Weight
Nimacimab Maintains Post-Treatment Weight Phase A Remove Drug Phase B ∆29.7% tirzepatide ‘rebound’ All drugs are investigational and subject to regulatory approval. ∆7.4% nimacimab ‘rebound’ 31 © 2025 Skye Bioscience, Inc.
Slide 29: Nimacimab Prevents Rebound And Shows Significant Potential As Maintenance Therapy
Nimacimab Prevents Rebound And Shows Significant Potential As Maintenance Therapy Phase A Switch Dosing Phase B ∆29.7% tirzepatide ‘rebound’ All drugs are investigational and subject to regulatory approval. ∆12.8% nimacimab ‘maintenance’ 32 © 2025 Skye Bioscience, Inc.
Slide 30: Nimacimab Improves Quality of Body Composition
Nimacimab Improves Quality of Body Composition Reduced fat mass while improved thermogenesis in BAT Body Composition Thermogenesis in Brown Adipose Tissue All drugs are investigational and subject to regulatory approval. Body weight and composition analyses were performed with two-way ANOVA repeated
Slide 31: Summary of Initial Nimacimab Studies
Summary of Initial Nimacimab Studies • Nimacimab is a humanized anti-CB1 antibody with key differentiators • Highly restricted to peripheral tissues (orders of magnitude beyond small molecules) • Binds to allosteric site on CB1 – a non-competitive antagonist and an inverse agonist • Maintains potenc
Slide 32: 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 33: Clinical & Regulatory
skye Clinical & Regulatory CBeyérid’ A ee .2.
Slide 34: 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 35: 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 36: CBeyond Phase 2a 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 37: Anticipated Clinical and Regulatory Milestones
Anticipated 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
Slide 38: What to Expect from CBeyond
What to Expect from CBeyond Clinical proof-of-concept that peripheral CB1 inhibition is differentiated and complementary to GLP-1s Endpoint What It Tells Us Why It Matters 5-8% WL at 26 weeks is a strong % Weight Loss (26 wks) Mono Direct signal of efficacy signal of efficacy with potentially greate
Slide 39: Review of target product profile and primary research insights
Review of target product profile and primary research insights
Slide 40: 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 Population to GLP-1 therapy after reaching a
Slide 41: 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 42: Obesity Treatment Paradigm
Obesity Treatment Paradigm Following lifestyle interventions, overweight and obese individuals are eligible for GLP-1 receptor agonists prior to bariatric procedures for patients with morbid obesity Treatment Paradigm Key Considerations • Inability to Reach Target Weight Loss Goal: Patients unable t
Slide 43: Obesity Unmet Needs
Obesity Unmet Needs Despite approvals of Zepbound and Wegovy, significant unmet needs remain for alternative treatments that preserve muscle, minimize side effects, offer a more convenient RoA, or provide easier access • Increased Loss of Lean Mass: While approved therapies are adequately effective,
Slide 44: 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 P2, and 29 P1 programs are primarily focused on GLP-1s; only 3 known CB1 assets in clinical development Unique Competitors in the U.S. Obesity Clinical Pipeline Key Pipeline Insig
Slide 45: Summarized Primary Research Insights
Summarized Primary Research Insights KOLs believe CB1 inhibitors are well-positioned to provide benefit to select patients given the favorable safety profile and acceptable efficacy Current Management Paradigm Unmet Needs KOLs indicate that most pharmacologically- Despite satisfaction with GLP-1 RAs
Slide 46: Heterogeneous Overweight Population Requires Different Treatment Options
Heterogeneous Overweight Population Requires Different Treatment Options Significant (20%+) weight reduction demonstrated by GLP-1s is not therapeutically appropriate for all obese patients Prevalence of Overweight and Obesity Among US Adults Obesity is Highly NHANES; 2017-2018 Heterogeneous; Many S
Slide 47: HCP-reported Nimacimab Addressable Pt Segments (1 of 2)
HCP-reported Nimacimab Addressable Pt Segments (1 of 2) Physicians identify numerous additional nimacimab use cases across treatment settings; HCPs believe nimacimab may address select unmet needs that current and future agents may not Most Relevant Patient Characteristics for Monotherapy • GLP non-
Slide 48: HCP-reported Nimacimab Addressable Pt Segments (2 of 2)
HCP-reported Nimacimab Addressable Pt Segments (2 of 2) In combination with incretin-based therapies, HCPs believe Nimacimab will be most appropriate for patients requiring significant weight loss Most Likely Candidate for Nimacimab Combination • Class 3 patients who require significant weight loss
Slide 49: 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 1 Robust IP, Life-Cycle and Development Strategy Planned nimacimab EOP2 by 2027 and IP/composition of matter protection through 2035* 2 Novel Biologi
Slide 50: Select Financial Figures & Metrics
Select Financial Figures & Metrics Stock Information • $107M in equity capital raised since Listed: Nasdaq SKYE August 2023 Stock Price1 $3.89 • Supported by top-tier specialist life All drugs are investigational and subject to regulatory approval. science investors Shares Outstanding2 31.0M • Funde
Slide 51: 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 52: Please learn more or contact us at
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 53: 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 54: Obesity 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 55: 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 56: 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