Cyclo Therapeutics : Scientific Presentation

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Scientific Presentation December 2023

Forward-Looking Statements

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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.

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Niemann-Pick

Disease Type C

2 Completed Studies (101 and 201)

Ongoing Long-Term Extension Study (102)

Ongoing Pivotal Phase 3 Study (

, 301)

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Trappsol® Cyclo™ as a potential therapy for NPC

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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-clinicaldata: 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.

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).

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Trappsol® Cyclo™	5
Mechanism of Action: Mobilizing lysosomal cholesterol (NPC)

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).

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Current status of product development for Trappsol® Cyclo™ Pre-clinicalpublished data and 4 clinical studies

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• Study CTD-TCNPC-101(NCT02939547): A Phase I study to evaluate the single and multiple-dose pharmacokinetics of intravenous Trappsol Cyclo (HPβCD) in patients with Niemann-Pick disease Type C (NPC1) and the effects of dosing upon biomarkers of NPC disease (1 site in the US) has completed. Final Clinical Study Report submitted September 24, 2020
• Study CTD-TCNPC-201(NCT02912793): A Phase 1/2 study to evaluate the safety and pharmacokinetics of intravenous
  Trappsol Cyclo (HPβCD) in patients with NPC1 and the pharmacodynamic effects of treatment upon markers of cholesterol metabolism and clinical outcomes (United Kingdom and Israel). Final Clinical Study Report submitted November 9, 2021.
• Study CTD-TCNPC-102(NCT03893071): An open-label extension study of the long-term safety and efficacy of intravenous
  Trappsol Cyclo (HPβCD) in patients with NPC1. Ongoing.
• Study CTD-TCNPC-301(NCT04860960): A multicenter, double-blind, randomized, placebo-controlled pivotal trial to evaluate the safety, tolerability, and efficacy of 2000 mg/kg of Trappsol Cyclo (administration as a slow infusion over 6.5 hours every 2 weeks) and standard of care (SOC) compared to placebo and SOC in patients with NPC. Ongoing.

1. Sub-studyunder CTD-TCNPC-301(EMEA-002839-PIP01-20):A multicenter sub-studyin patients newborn to <3 years of age to evaluate the safety of 2,000mg/kg of Trappsol Cyclo (administration as a slow infusion over 6.5 hours every 2 weeks) and to obtain descriptive data regarding global severity and improvement in response to Trappsol Cyclo from both Investigator and patient perspectives (Clinical Global Impression - Severity [CGI-S],Clinical Global Impression of Change [CGI-C],Caregiver's Global Impression Scales [CaGI-S],Caregiver Global Impression of Change [CaGI-C],and Caregiver Global Impression of Change 24 hours after infusion [CaGI-C24]).Ongoing.

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Pre-clinical data	7
Safe and efficient HPβCD target concentration within the brain

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

Figure courtesy of David Begley, Kings College, London

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

1. Peake KB, Vance JE; J Biological Chemistry (2012)
2. Tsamaloukas A, et al; Biophys J (2005)
3. Taylor AM, etal; JLR: (2012)

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 dimers3

remaining in membrane (%)

Lipid

ß-cyclodextrin (mM)

NASDAQ: CYTH	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
cyclotherapeutics.com

Pre-clinical intravenous application and Study CTD-TCNPC-201 data	8
Blood brain barrier transfer of saccharide compounds and 201 PK

• 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 Cmax (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);	HPβCD (Trappsol® Cyclo™)
4	Hastings C, et al; Molecular Genetics and Metabolism Reports (2023)
5	Gaohua L, et al; Drug Metab Pharmacokin (2016)

Plasma Pharmacokinetic Data of Trappsol Cyclo from CTD-TCNPC-201 Study

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.

L-Glucose

Sucrose

Raffinose

Inulin 

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Pre-clinical data from mice over 0hr-12hr	9
Immediate effect: mobilization of cholesterol from lysosomes in liver

• 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

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

Taylor AM, etal; JLR: (2012); Cyclodextrin mediates rapid changes in lipid balance in Npc1-/- mice without carrying cholesterol through the bloodstream;

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Phase 1 Study (CTD-TCNPC-101)

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Clearance of trapped liver cholesterol following 14 weeks of treatment

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

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

1500	Baseline	14 Weeks	Baseline	14 Weeks	Baseline	14 Weeks
		2500		2500
Mg/kg			Mg/kg		Mg/kg
(Mild)			(Marked)		(Marked)
Reduction			Reduction		Reduction

The lack of light blue represents the clearing of cholesterol from cells

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