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NASDAQ: CYTH cyclotherapeutics.com
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NASDAQ: CYTH cyclotherapeutics.com Forward-Looking Statements Some of the information in this presentation relates to future events or future business and financial performance. Such statements constitute forward-looking information within the meaning of the Private Securities Litigation Act of 1995. Such statements can be only predictions and the actual events or results may differ from those discussed due to, among other things, the risks described in the public filings and other publications of Cyclo Therapeutics, Inc. Forward-looking statements are identified by words such as “anticipates”, “projects”, “expects”, “plans”, “intends”, “believes”, “estimates”,“target”, and other similar expressions that indicate trends and future events. The market data and certain other statistical information used throughout this presentation are based on independent industry publications, governmental publications, reports by market research firms or other independent sources. Some data are also based on the Company’s good faith estimates. In addition, this presentation includes summaries of scientific activities and outcomes that have been condensed to aid the reader in gaining general understanding. The information about Cyclo Therapeutics, Inc. and its subsidiaries is solely for information purposes and is not to be construed as an offer to sell or the solicitation of an offer to buy any security in any state. Factors that could cause the Company’s results to differ materially from those expressed in forward looking statements include, without limitation, the Company’s need for additional capital; the Company’s reliance on its Trappsol® Cyclo product, which may never receive regulatory approval; the Company’s ability to commercialize any of its proposed drug products if it receives regulatory approval; the outcome of the Company’s clinical trials, which may not support the Company’s product claims or may result in adverse side effects; the cost and timing of the Company’s clinical trials; the Company’s reliance on third parties to conduct clinical trials and to produce its products; and other risks associated with being a clinical stage biotechnology company. This presentation is not to be copied, transmitted, displayed, distributed (for compensation or otherwise), or altered in any way without the prior written consent of Cyclo Therapeutics, Inc. 2
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NASDAQ: CYTH cyclotherapeutics.com 3 Company Snapshot 3 1. April 2021, Tessellon Inc. (former Kantar Health experts with 25+ years of epidemiology and forecasting experience), (www.Tessellon.com); Exhaustive literature search with a broad range of MESH terms in United States + 79 other countries. 2. https://www.alz.org/alzheimers-dementia/facts-figures Who: In 1990, the company was formed as Specialty Fine Chemical business specializing in cyclodextrins. In 2014, the business was expanded into a biotechnology company dedicated to developing life-changing medicines through science and innovation for patients and families living with challenging diseases. What: Trappsol® Cyclo is a proprietary formulation of hydroxypropyl beta cyclodextrin and in multiple clinical studies has shown encouraging results to effectively manage the transportation of cholesterol. Why: Because cholesterol is so important to the normal function of our cells, its synthesis and degradation is tightly controlled by an array of cellular processes. When there is an imbalance in cholesterol synthesis or metabolism, cells and organs may not function properly, leading to disease or death. How: Trappsol® Cyclo , with its cyclic structure, facilitates the transport of accumulated cholesterol out of cellular lysosomes so it can be further processed and excreted out of cells. Currently Targeting 2 Serious Diseases with Unmet Medical Need Niemann-Pick Disease Type C Fatal and progressive genetic disorder Orphan indication affecting >9,000 in 80 countries (~400 in U.S. / 320 EU5) 1 Alzheimer’s Disease 6th leading cause of death affecting 5 million people in the U.S.2 Platform technology has potential to fuel pipeline expansion opportunities
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NASDAQ: CYTH cyclotherapeutics.com Platform Technology Pipeline: Trappsol® Cyclo allows for a multiple shots on goal model 4 Program Indication Preclinical Phase 1 Phase 2 Phase 3 Milestones Trappsol® Cyclo Niemann-Pick Disease Type C Enrollment completed May 2024; 48-week comparative interim analysis planned for H1 2025 Trappsol® Cyclo Alzheimer’s Disease First patient enrolled and dosed in Q1 2023 for Phase 2b study Orphan Drug Designation in U.S. | Fast Track Status in U.S. | Potential for Priority Review Voucher (PRV) in U.S Orphan Designation in EU | EMA Pediatric Investigational Plan Adopted Ongoing Collaboration with University of the Witwatersrand, Johannesburg to Advance Trappsol® Cyclo Platform and Explore Pipeline Expansion Opportunities If 48-Week Data Demonstrate Significance, NDA and EMA Submission Targeted for 2H 2025
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NASDAQ: CYTH cyclotherapeutics.com Leadership Team with Proven Experience 5 Michael Lisjak Chief Regulatory Officer Joshua M. Fine Chief Financial Officer Lori Gorski Global Head of Patient Advocacy N. Scott Fine Chief Executive Officer & Director Jeffrey L. Tate, Ph.D. Chief Operating Officer, Chief Quality Officer & Director Karen Mullen, FFPM Interim Chief Medical Officer
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NASDAQ: CYTH cyclotherapeutics.com Niemann-Pick Disease Type C Ongoing Pivotal Phase 3 Study 6
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NASDAQ: CYTH cyclotherapeutics.com NPC: A Debilitating Disease with Fatal Outcomes • Rare, fatal and progressive genetic disorder affecting the brain, liver, spleen and lungs • Characterized by a defect in the NPC1 protein • Cholesterol and lipids accumulate in cells of major organs and tissues • Leading to cell and tissue dysfunction 7 ~ 3% are age 3 and below ~ 97% are age 3 and above ~ 60% age 16 and above 1/100,000 (~35 per year in U.S.) Early Infantile (2m-2): 4.6y Late Infantile (3-6): 9.4y Juvenile (7-15): 15.4y Adolescent/Adult (16+): 12.2y Incidences Of Diagnosis Median Survival 1: Data on file Cyclo Therapeutics *Scope: United States + 79 other countries; *Commissioned Tessellon Inc – former Kantar Health experts with 25+ years of epidemiology and forecasting experience, (www.Tessellon.com); *Exhaustive literature search with a broad range of MESH terms. U.S. Approved NPC Therapies2 EU Approved Therapy with No Systemic Effects1 Market Opportunity1 United States: $300 Million | Worldwide: $600 Million
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NASDAQ: CYTH cyclotherapeutics.com Conclusion The data obtained from preclinical studies and Cyclo Therapeutics completed and ongoing clinical studies suggest Trappsol® Cyclo is well-tolerated and has the potential to treat both the systemic and neurological symptoms of NPC. The data from our early phase studies and OLE are currently being confirmed in our ongoing Phase 3 Study (CTD-TCNPC-301). 8 Trappsol® Cyclo as a Potential Therapy for NPC Suggestive evidence of safety and systemic and neurological benefit • Mechanism of Action: Trappsol® Cyclo , with its cyclic structure, facilitates the transport of cholesterol between cells and subcellular structures thus circumventing blockades and enabling the normal function of cells and tissues. • Pre-clinical data: Demonstrates the amount of HPβCD getting into the brain is at a safe and efficient concentration in order to enhance transfer of cholesterol between (intra)cellular membranes and therefore supportive of Trappsol® Cyclo having a potential safe and effective benefit for the neurological symptoms of NPC. • Phase 1 Study (CTD-TCNPC-101): Data suggests that Trappsol® Cyclo has an acceptable well-tolerated safety profile and demonstrates clearance of trapped liver cholesterol, indicates that cholesterol turnover is normalized and cholesterol synthesis rate adjusted for the whole body, shows reduced changes in metabolite level is indicative of reduced cholesterol storage and indicates normalization of cholesterol storage in brain neurons. These data are suggestive of a potential benefit for both the systemic and neurological symptoms of NPC. • Phase 2 Study (CTD-TCNPC-201): Data demonstrates that Trappsol® Cyclo has an acceptable well-tolerated safety profile and that a potential therapeutic benefit may be observed at or before 48 weeks of treatment compared to disease progression. Although studied in a small patient sample size, provides compelling evidence of disease stabilization or improvement for the 5D-NPC-SS, CGI-I and SARA scales. • Ongoing Extension Study (CTD-TCNPC-102): Provides long-term safety data demonstrating the product is well-tolerated along with data suggestive of durability of effect.
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NASDAQ: CYTH cyclotherapeutics.com Trappsol® Cyclo 9 Enables the Effective Transport of Cholesterol Out of Cells Maetzel et al., 2014 Source : Study 101 Cholesterol as measured by Filipin staining at Baseline and after 7 doses over 14 weeks The lack of light blue represents the clearing of cholesterol from cells Baseline 14 Weeks Baseline 14 Weeks Baseline 14 Weeks 1500 Mg/kg (Mild) Reduction Under normal conditions, NPC1, located on the late endosomal/lysosomal (LE/L) compartments, regulates cholesterol efflux (Maetzel et al, 2014) (see left panel below). In NPC, mutations in the NPC1 gene on both alleles lead to accumulation of cholesterol in the LE/L compartments by inhibiting its efflux, and to a block in autophagic flux, which causes accumulation of autophagosomes and autophagy substrate due to impaired formation of amphisomes (see middle panel below). Trappsol® Cyclo mediated cholesterol release independent of the function of both NPC1 and NPC2 proteins, circumventing blockades in cholesterol transport, and therefore has the potential to bring significant benefit to patients with NPC (see right panel below). 2500 Mg/kg (Marked) Reduction 2500 Mg/kg (Marked) Reduction
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NASDAQ: CYTH cyclotherapeutics.com 10 • After IV infusion, the drug is detectable in the cerebrospinal fluid within hours after the start of infusion • Cholesterol synthesis and metabolism affected, and cholesterol cleared from cells, mimicking effects from nonclinical studies (in vitro and in vivo) in NPC models • Publication to the Molecular Genetics and Metabolism Report: Intravenous 2-hydroxypropyl-β- cyclodextrin (Trappsol® Cyclo ) demonstrates biological activity and impacts cholesterol metabolism in the central nervous system and peripheral tissues in adult subjects with Niemann-Pick Disease Type C1: Results of a phase 1 trial (2022) Study 101 Phase 1 study in NPC patients age 18 years and older showed Trappsol® Cyclo was well- tolerated with an acceptable safety and tolerability profile Study 102 Has the potential to treat both the systemic and neurological manifestations of NPC and is well-tolerated with an acceptable safety and tolerability profile • The available data from the OLE study indicate that the study medication has an acceptable tolerability profile • Although the number of patients is small, the data for the 5-Domain clinical severity scores (5-D-NPC-CSS) does show a potential for stabilization and slower disease progression following administration of Trappsol® Cyclo than may be otherwise expected based on published literature on the natural course of the disease over the longer term, therefore providing evidence of durability of effect Study 201 Consistent pharmacodynamic effects and safety profile observed in a 48-week Phase 1/2 study in NPC patients aged 2 years and older • 100% of patients assessed by treating physicians to be either stable or improved • 8 of 9 (89%) completer patients showed Improvements over disease progression in the 17D-NPC-SS • Based on totality of data from the Phase 1 and Phase 2 studies, the 2000 mg/kg dose was selected for the Phase 3 study • Publication to the Molecular Genetics and Metabolism Report: The Long-term administration of intravenous Trappsol® Cyclo (HPβCD) results in clinical benefits and stabilization or slowing of disease progression in patients with Niemann-Pick disease type C1: Results of an international 48-week Phase I/II trial (2023) Trappsol® Cyclo Summary of Completed Studies and OLE
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NASDAQ: CYTH cyclotherapeutics.com 11 • Potential therapeutic benefit which may be observed at or before 48 weeks of treatment compared to disease progression • The small cohort size (9 patients) limits extensive analysis of the changes within the study • Importantly, transient variations cannot be separated from disease progression, but are expected to be reduced in a larger cohort (the ongoing Phase 3 CTD-TCNPC-301) Phase 1/2 Study (CTD-TCNPC-201) Data Included Key Outcomes Data represented in above graph is from different studies. Solid line is from Cyclo Therapeutics CTD-TCNPC-201 Study. The dashed lines are disease progression rates identified from the following 3 sources: • In the most recent studies on disease progression in 2 reference patient cohorts, both with and without baseline treatment by miglustat, an average annual progression of 2.94 points (21 patients: Ory, 2017) and 2.92 points (36 patients: Mengel, 2020) on the 17D scale was found, with the 5D-NPC-CSS scale showing a progress of 1.5 units per year (Mengel, 2020). • The placebo group in the Orphazyme Phase 2/3 study (16 patients: Mengel, 2021) showed an annual progression on the 5D-scale of 2.15 points and on the 17D-scale (excluding hearing domains) of 2.8 points. The 17D-NPC-CSS parameter is in good agreement with the 2 natural history cohorts mentioned above, while the 5D-NPC-CSS parameter is higher than in the 2 earlier studies (Mengel, 2021). • The predicted disease progression of Cyclo Therapeutics Study CTD-TCNPC-201 cohort (completers) without treatment, based on 50% of baseline ASIS. • 9 completers (2 patients in the 1500 mg/kg group; 4 patients in the 2000 mg/kg group; 3 patients in the 2500 mg/kg group) • Three patients were excluded from this analysis due to 1 only having baseline data and 2 patients discontinued prior to Week 48 for non-safety reasons Potential benefit may be observed at or before 48 weeks
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NASDAQ: CYTH cyclotherapeutics.com 12 • In a disease characterized by linear disease progression, treatment with Trappsol Cyclo resulted in the stabilization or improvement in 6 of 9 (67%) completer patients on the 5D- NPC-SS • 8 of 9 (89%) completer patients showed Improvements over disease progression (2.15 points per annum) in the 5D-NPC- SS • 9 of 9 (100%) completer patients exhibited stabilized or improved in CGI-I ratings, a clear indicator of efficacy in NPC- 1 patients Reference cohorts from the literature 2.15 points per annum (Mengel, 2021) Phase 1/2 Study (CTD-TCNPC-201): Continued Individual data suggestive of potential benefit on 5D-NPC-SS & CGI-I Data Included Key Outcomes • 9 completers (2 patients in the 1500 mg/kg group; 4 patients in the 2000 mg/kg group; 3 patients in the 2500 mg/kg group) • Three patients were excluded from this analysis due to 1 only having baseline data and 2 patients discontinued prior to Week 48 for non-safety reasons
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NASDAQ: CYTH cyclotherapeutics.com 13 • Multiple domains are reflected in these average scores: gait, stance, sitting, speech, finger chase (L/R), nose-finger (L/R), fast alt hands (L/R), and heel shin (L/R) • Patients who received (2500 mg/kg or 2000 mg/kg), exhibit stabilized or improved scores for the SARA domains considered (gait, stance, sitting, and speech) compared to baseline • Higher dose (2500 mg/kg) suggestively improved gait, stance, and speech at 48 weeks (Figure A-D) • Lower dose (2000 mg/kg) suggestively improved stance and stabilized sitting and speech at 48 weeks (Figure E-H) • Potential benefits, at least descriptively, are dose-ordered and higher exposures may produce a more consistently favorable effect, acknowledging small sample size and heterogeneity of patient presentation • Scores for individual SARA domains on a group level for multiple doses: 2500 mg/kg, 2000 mg/kg, and 1500 mg/kg. Descriptive presentation of patient-level data focused on the following SARA domains: gait, stance, sitting, and speech. Patients receiving a 1,500 mg/kg dose were not included in subsequent analyses due to incomplete or missing data at 48 weeks Data Included Key Outcomes Phase 1/2 Study (CTD-TCNPC-201): Continued Dosage data suggestive of potential benefit on SARA, an exploratory measure
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NASDAQ: CYTH cyclotherapeutics.com Expected disease progression has been identified from the following source: • The placebo group in the Orphazyme Phase 2/3 study (16 patients: Mengel, 2021) showed an annual progression on the 5D-scale of 2.15 points and on the 17D-scale (excluding hearing domains) of 2.8 points. • 3 patients remain on active treatment, all receiving 1,500 mg/kg every 2-weeks via in- home infusions Data Included is from an August 2023 data cut • All 5 patients exhibited slowing of disease progression, with some patients showing stabilization or improvement • Suggestive evidence of Durability of effect for Trappsol® Cyclo as a chronic medication • The Safety and tolerability remains consistent with completed and ongoing trials and has been well tolerated Key Outcomes from the OLE Efficacy data from Ongoing Long-Term Extension (OLE) Study Ongoing Long-Term Extension (OLE) Study (CTD-TCNPC-102) Suggestive evidence of durability of effect 14 Patients 001-11 and 001-10 have had no treatment breaks to date. Patient 001-04 had a break of 38 wks, Patient 001-02 had a break of 54wks and Patient 001-01 had breaks of 65wks and 55wks.
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NASDAQ: CYTH cyclotherapeutics.com 15 • Treatment-Emergent Adverse Events majority mild to moderate in severity, manageable and monitorable and most considered unrelated to Trappsol® Cyclo • No evidence of any untoward effects of Trappsol® Cyclo on core organ systems (cardiovascular, respiratory, renal, hepatic, gastrointestinal systems or CNS) • The observed safety and tolerability profile consistent across studies and treatment duration, irrespectively of age spectrum and disease severity • Hearing loss and infusion reactions (most localized) are adverse events of interest • Events of hearing loss resolved in most patients, with hearing returning to baseline levels or improved and stabilized while patients continued on study drug • A degree of hearing impairment remained at the last available auditory assessment in a limited number of patients • The effect on hearing will continue to be monitored closely in the ongoing studies Safety from Completed and Ongoing Long-term Treatment Suggestive of a benefit risk that is safe and well-tolerated
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NASDAQ: CYTH cyclotherapeutics.com 16 Topline Data from 48-week Interim Analysis of 104 Enrolled Patients Targeted for H1 2025 If 48-week Data Demonstrate Significance, NDA and EMA Submission Targeted for 2H 2025 Number of Subjects 104 Current Sites 30+ across 14 countries Duration1 96-week trial. Per Health Authority advice, a 48-week comparative interim analysis can be conducted to demonstrate statistical significance. Dose 2000 mg/kg via IV infusion Primary Endpoint NPC Composite Severity Score Secondary Endpoints SCAFI, Swallow, Vineland-2 Exploratory Endpoints Inclusive of speech, liver and lung function Substudy (Patients 0-3)2 Requested as part of our adopted PIP to potentially treat as a prophylactic treatment option. United States, United Kingdom, Italy, Germany, Spain, Poland, Ukraine, Israel, Turkey, Argentina, Brazil, Australia, Taiwan and Saudi Arabia Ongoing Pivotal Phase 3 Study in Niemann-Pick Disease Type C 1 Should the comparative interim analysis at 48-weeks demonstrate significance, Cyclo will submit the NDA to the FDA and MAA to the EMA based on 48-week data. 2 Substudy is only being conducted ex-US. Patients are not randomized and all patients in the 0-3 cohort receive Trappsol® Cyclo .
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NASDAQ: CYTH cyclotherapeutics.com Significant Competitive Advantages 17 Company* Indication Preclinical Phase 1 Phase 2 Phase 3 Potential Indication (Systemic and Neurological) Safety Profile Summary Trappsol® Cyclo (Intravenous every 2 weeks, home infusions) Met all primary endpoints of the Ph1 and Ph1/2 showing favorable safety and efficacy. Last Patient In for 48-week comparative interim analysis May 2024, topline date 1H 2025. Zavesca (Oral 3 times daily) FDA: Data did not support benefit risk. Off-label in US. EMA: Approved January 2009. IB1001 (Oral 3 times daily) FDA: Approved AQNEURSA as a stand-alone therapy for Niemann-Pick Type C in adults and pediatric patients weighing ≥15 kg. EMA: No timing provided. Arimoclomol (Oral 3 times daily) FDA: Approval received on September 20, 2024 for MIPLYFFA (arimoclomol) in combination with miglustat. Additionally, they received a rare pediatric disease priority review voucher (PRV) in conjunction with the approval. EMA: No timing provided. Adrabetadex (VTS-270) (Intrathecal every 2 weeks) MNK concluded program January 20, 2021 noting the benefit risk is negative. Mandos received Court Approval to buy from MNK June 29, 2021. FDA has not found drug to be safe and effective for use to treat NPC1 or for any other use. AZ-3102 (Oral) TBD TBD A Phase 2 12-week study (Rainbow) for GM2 gangliosidosis and NPC to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics was completed March 2024. Topline data readout announced July 2024 and Phase 3 Trial(s) planned for 2025. Differentiation Key: - Optimal - Moderate - Weak * There are other companies in pre-clinical which we continue to monitor. As they mature, we will add to the above table as appropriate.
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NASDAQ: CYTH cyclotherapeutics.com Alzheimer’s Disease Ongoing Phase 2b Study 18
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NASDAQ: CYTH cyclotherapeutics.com Commonality Across Target Neurodegenerative Diseases 19 Cholesterol Accumulation in Regions of Brain Elevated Levels of Tau in CSF Amyloid Plaques in the Brain Biologic Similarities Alzheimer’s Disease Secondary Tauopathy Niemann-Pick Disease Type C Primary Tauopathy Disease Manifestation Cognitive decline / dementia Premature death Clumsiness Progressive motor symptoms Ataxia, dystonia, dysarthria, dysphasia Psychiatric signs: psychosis, depression Weight loss Disease Manifestation Progressive cognitive decline / early dementia Premature death Clumsiness, gait disturbance Delayed motor milestones Progressive: ataxia, dystonia Seizures Weight loss
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NASDAQ: CYTH cyclotherapeutics.com 20 *Treating physician reported the 18-month score as a range between 24-26 1: Rate of MMSE decline in AD patients: Eldholm, RS et al, J. Alz. Disease, 61: 1221, 2018. Suh, GH et al., Intl. J. Geriatric Psychiatry, 19(9): 817, 2004. 12 15 18 21 24 27 30 0 3 7 9 12 14 18 MMSE Months Cyclo Patient Cognitively Normal = 30 Expected Decline of AD Patients * “The patient has shown cognitive and neurologic stability in serial examinations during this study that indicates possible benefit as there would be an expected measurable cognitive and functional decline over an 18-month period in persons with Alzheimer’s disease dementia,” Treating Physician Alzheimer’s Mini-Mental State Evaluation Performance1 Positive Results in Alzheimer Patient Under Compassionate Use Program FDA authorized use of Trappsol® Cyclo in geriatric patient 18 months of monthly IV infusion Disease did not progress Family reported less volatility and greater word- finding ability 18 months of data has led to development of Phase 2 protocol Preeminent Neuroscientist and World-Renowned Researcher, Cynthia A. Lemere, PhD Senior Advisor for Advancement of Alzheimer’s Disease Asset Trappsol® Cyclo for the Potential Treatment of Early Alzheimer’s Disease Targeting Reduction of Amyloid Beta and Tau
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NASDAQ: CYTH cyclotherapeutics.com 21 U.S. Multicenter, Randomized, Placebo-Controlled, Double-Blind, Parallel Group, 6-Month Study Number of Subjects ~90 Current Sites 6 + across two countries Duration 6 Months Dose Randomized across three study arms: 500 mg/kg or 1000 mg/kg of Trappsol® Cyclo and Placebo Study Endpoints Safety, Tolerability and Potential Efficacy Ongoing Phase 2b Study in Early Alzheimer’s Disease First Patient Enrolled and Dosed in Q1 2023 for Phase 2b Study
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NASDAQ: CYTH cyclotherapeutics.com Corporate Overview 22
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cyclotherapeutics.com Definitive Merger Agreement 23 Entered into a definitive merger agreement on August 22, 2024 to combine the two companies to focus on the development of Trappsol® Cyclo for the treatment of Niemann-Pick Disease Type C1 Financial Snapshot – Nasdaq: CYTH Cash Balance1 ~$0.9M Market Cap 2 ~$18M Shares Outstanding 3 ~28.7M 1: As of September 30, 2024 2: As of November 29, 2024 3: As of November 12, 2024
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cyclotherapeutics.com Investment Summary 24 Leveraging Over 3 Decades of Experience with Cyclodextrins to Advance Clinically De-risked Programs Towards Approval in Diseases with Unmet Medical Need Pipeline expansion into Alzheimer's Disease (AD), patent filed globally and is currently being executed First patient enrolled and dosed in Q1 2023 for Phase 2b study Multiple value-driving milestones expected Platform technology with opportunity to expand into multiple indications Leadership team with proven track-record in execution and value creation Enrollment completed Q2 2024; Topline data from the 48-week interim analysis of 104 enrolled patients is anticipated for H1 2025 Significant market opportunity with no approved therapy to treat both systemic and neurological manifestations of NPC FDA: Orphan Drug Designation (ODD), Fast-Track, Rare Pediatric Disease Designation, potential PRV; EMA: ODD and adopted PIP Strategic relationship with Rafael Holdings, Inc. provides financial and strategic guidance. $24M in committed capital. William Conkling, Rafael CEO and Dr. Vivien Wong, PhD have joined Cyclo Therapeutics’ Board Platform technology has demonstrated to be safe and effective with over 10 years of patient exposure
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NASDAQ: CYTH cyclotherapeutics.com 25 Appendix Completed Trials
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NASDAQ: CYTH cyclotherapeutics.com Neurologists & Geneticists Crucial Specialties in the Diagnosis of NPC (Return on Focus Patient Journey Interviews, January 2022) 26 5 4 1 0 1 2 3 4 5 6 Neurologist Genetecist Gastroenterologist Specialties of Diagnosing Physicians n=10
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NASDAQ: CYTH cyclotherapeutics.com 1 Peake KB, Vance JE; J Biological Chemistry (2012) 2 Tsamaloukas A, et al; Biophys J (2005) 3 Taylor AM, etal; JLR: (2012) HPβCD effects in cell culture system: • 0.1 mM HPβCD released cholesterol trapped in the lysosomes • 1 mM HPβCD primarily extracted cholesterol from the cell membrane • 10 mM HPβCD was profoundly toxic to neurons Effect of HPßCD (24 h) on cell cultures of neurons and astrocytes (mouse). At 10 mM HPßCD kills 100% of neurons (D), but not astrocytes (H) 1 Effect of increasing concentrations of ß-cyclodextrin on lipid membranes. Above 1 mM ß-cyclodextrin an increasing fraction of cholesterol is extracted from membranes (image modified) 2 Below 1mM HPβCD can partially move cholesterol out from cell membranes (one HPβCD interacts with one cholesterol molecule) This significantly enhances transfer of cholesterol between (intra)cellular membranes and provides an exit from lysosomes Abbove 1mM an increasing amount of cholesterol will be extracted from membranes (by two cyclodextrins per cholesterol) – this will damage sensitive cells At low concentrations effects of HPβCD and sulfobutyl-ß- CD in precinical models are similar. The latter compound cannot form dimers 3 ß-cyclodextrin (mM) Lipid remaining in membrane (%) Figure courtesy of David Begley, Kings College, London Pre-clinical Data Safe and efficient HPβCD target concentration within the brain 27
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NASDAQ: CYTH cyclotherapeutics.com • Rate of uptake of Trappsol® into liver cells was found to be similar to transfer over the BBB (10 µl/h/g – 20 µl/h/g) • Export of unesterified cholesterol from lysosomes until 12h from start of single HPßCD injection is about 3 mg/g of liver tissue • Exported cholesterol transiently stored as cholesterol ester in lipid droplets in the cytosol • Increase in cholesterol ester concentration in cytosol over 12h reflects decrease in lysosomal concentration • Note: Slow infusion of Trappsol® in humans makes an export of 3 mg – 6 mg of cholesterol / g of liver tissue per treatment cycle likely 28 Taylor AM, etal; JLR: (2012); Cyclodextrin mediates rapid changes in lipid balance in Npc1-/- mice without carrying cholesterol through the bloodstream; About 3 mg/g of unesterified cholesterol removed from liver lysosomes @12h about 2 mg/g of esterified cholesterol transiently stored in cytosol of hepatocytes Pre-clinical Data from Mice Over 0hr-12hr Immediate effect: mobilization of cholesterol from lysosomes in liver
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NASDAQ: CYTH cyclotherapeutics.com Inulin L-Glucose Sucrose RaffinoseHPβCD (Trappsol® Cyclo ) 29 • Under the extended infusion used in clinical trials for Trappsol® Cyclo , a stable concentration of about 1 mM is reached in plasma • T1/2 Plasma app 2h; T1/2 CNS app 6h (human and mouse data) • Most mono-, oligo-, and polysaccharides show moderate transfer over the BBB. Transfer happens by micropinocytosis (transport in small vesicles, largely independent from molecular weight 2, 3) • Four saccharide compounds investigated for BBB transport 2, 3 are shown below. Uptake over the BBB was observed at 0.1 µl/g/min to 0.2 µl/g/min. Trappsol®Cyclo fits into the compound class and into the molecular weight range • Under the conditions used in the Trappsol® Cyclo NPC Phase 1 trial a peak concentration of 40 µM to 80 µM Trappsol® is expected in the CNS • The concentrations found in lumbar CSF of patients at the end of treatment of about 30 µM 1, 4 are in line with this value A ratio of C max (cranial) to Cmax (lumbar) of 2 – 4 is assumed in literature 5 BBB: Blood Brain Barrier; CSF: Cerebrospinal Fluid 1 Hastings C, et al; Molecular Genetics and Metabolism (2022) 2 Amtorp O; Acta Physiol Scand (1980); 3 Lucchesi KJ, Gosselin RE; Am J Physiol (1990); 4 Hastings C, et al; Molecular Genetics and Metabolism Reports (2023) 5 Gaohua L, et al; Drug Metab Pharmacokin (2016) Mean (SD) Plasma Concentrations (ng/mL) of HPβCD versus Time in Patients Following an Initial IV Infusion of Trappsol® over 8 hours at 1500, 2000, or 2500 mg/kg1. The 2’000 mg/kg dose was selected for the phase 3 trial. Plasma Pharmacokinetic Data of Trappsol Cyclo from CTD-TCNPC-201 Study Pre-clinical Intravenous Application and Study CTD-TCNPC-201 Data Blood brain barrier transfer of saccharide compounds and 201 PK
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NASDAQ: CYTH cyclotherapeutics.com 30 The percentage of filipin III (filipin) - stained positive tissue area in liver tissue samples from 8 NPC1 subjects at Baseline and 2 weeks after the seventh HPβCD infusion The lack of light blue represents the clearing of cholesterol from cells Baseline 14 Weeks 1500 Mg/kg (Mild) Reduction 2500 Mg/kg (Marked) Reduction 2500 Mg/kg (Marked) Reduction Baseline 14 Weeks Baseline 14 Weeks Representative images of filipin staining of liver tissue of unesterified lysosomal cholesterol at Baseline and 14weeks post-treatment with low (1500 mg/kg) and high (2500 mg/kg) doses Phase 1 Study (CTD-TCNPC-101) Clearance of trapped liver cholesterol following 14 weeks of treatment
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NASDAQ: CYTH cyclotherapeutics.com 31 • Lathosterol is a precursor of whole- body cholesterol • Observed pattern of serum lathosterol levels in week 1 – 2 consistent with reduction in cholesterol synthesis following release of trapped cholesterol • New equilibrium following repeated infusions (week 13 – 14) • Indicates that cholesterol turnover normalized and cholesterol synthesis rate adjusted Week 1/2 Week 13/14 Phase 1 Study (CTD-TCNPC-101): Lathosterol Biomarker Single infusion reduces cholesterol biosynthesis
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NASDAQ: CYTH cyclotherapeutics.com 32 • Rapid onset of effects of Trappsol Cyclo with increase in cholesterol catabolism within days and lasting for more than 1 week post infusion • Peak in cholesterol metabolite supports extensive release of trapped cholesterol • Following 12 weeks of treatment, reduced changes in metabolite level indicative of reduced cholesterol storage Note: In mice, there is a clear transient increase of 7-α-hydroxycholesterol, prime cholesterol degradation product; not measured in humans due to significant diurnal variation. Phase 1 Study (CTD-TCNPC-101): 4β-hydroxycholesterol Biomarker Single infusion increases cholesterol catabolism
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NASDAQ: CYTH cyclotherapeutics.com • 24S-hydroxycholesterol, a cholesterol metabolite from neurons in the CNS. Crosses the BBB and measured in serum • Increases in serum 24S-hydroxycholesterol following initial administration of HPβCD • Reduction of effect over 14 weeks, indicates normalization of cholesterol storage in brain neurons The mean serum 24(S)-hydroxycholesterol (ng/L) level increased in subjects from both dose groups after the first (Week 1 Day 2, W1D2) and seventh (Week 12 Day 3, W12D3) infusions with HPβCD and then returned to baseline levels. The peak following the seventh infusion was reduced compared to that of the first infusion. Hastings et al. 2022 Phase 1 Study (CTD-TCNPC-101): 24S-Hydroxycholesterol Biomarker Increased cholesterol catabolism in brain neurons 33
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NASDAQ: CYTH cyclotherapeutics.com 34 Phase 1/2 Study (CTD-TCNPC-201): Continued Data suggestive of utility of the 5D-NPC-SS alongside secondary endpoints • On a patient-specific level, no consistent treatment patterns were observed across 5D-NPC-SS domains at 48 weeks • Although some domains were universally stabilized (i.e., swallowing), each patient stabilized or improved on a unique combination of assessments that contributed to their composite score • Cyclo Therapeutics believes this can be attributed to the diverse ages of enrolled patients (2-39 years of age) and reflects the heterogeneity of disease stage and progression, yielding differential sensitivity to drug effect based upon patient phenotype • Data suggest the utility of the 5D-NPC-SS composite score alongside planned secondary outcome measures (i.e., Spinocerebellar Ataxia Functional Index [SCAFI], Vineland-2, PAS) to holistically observe disease progression across diverse patient population, consistent with those randomized and approaching a 48-week endpoint in the ongoing Phase 3 (CTD-TCNPC-301) • 9 completers (2 patients in the 1500 mg/kg group; 4 patients in the 2000 mg/kg group; 3 patients in the 2500 mg/kg group) • Three patients were excluded from this analysis due to 1 only having baseline data and 2 patients discontinued prior to Week 48 for non-safety reasons Data Included Key Outcomes
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NASDAQ: CYTH cyclotherapeutics.com Thank you!