Therapeutics

Trappsol® Cyclo™

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Overview

Name: Trappsol® Cyclo™
Synonyms: HP-beta-CD, HPbetaCD
Chemical Name: 2-hydroxypropyl-beta-cyclodextrin
Therapy Type: Other
Target Type: Cholesterol
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 2)
Company: Cyclo Therapeutics, Inc.

Background

Trappsol® Cyclo™ is a proprietary, intravenous formulation of 2-hydroxypropyl-β-cyclodextrin in development to treat diseases associated with impaired cholesterol metabolism, including Alzheimer's disease. This cyclic oligosaccharide sequesters cholesterol, solubilizing it and extracting it from cells.

Produced from starch by enzymatic conversion, cyclodextrins are widely used in food, cosmetics, and for drug delivery, where they confer solubility and stability, and improve bioavailability. When taken by mouth, HP-β-CD is generally considered safe, but animal studies revealed a potential for damage to hearing and kidney function, especially when the drug is given by infusion or injection (e.g. Cronin et al., 2015; Scantlebery et al., 2019). 

Trappsol® Cyclo™ is being evaluated in a Phase 3 trial to treat Niemann-Pick disease type C, a rare genetic disorder that leads to cholesterol accumulation in lysosomes, neurodegeneration, and death in childhood or adolescence. NPC shares features with Alzheimer's disease, including tau tangles, amyloid deposition, and cognitive decline (Malnar et al., 2014). In animal models of NPC, HP-β-CD removed sequestered cholesterol from lysosomes of multiple organs including the brain, delayed symptom onset, and prolonged life (e.g. Davidson et al., 2009; Liu et al., 2010).

In preclinical work related to AD, HP-β-CD injections improved spatial learning and memory deficits, and lessened amyloid plaque deposition and tau-containing dystrophic neurites in the Tg19959 mouse amyloidosis model. The drug reduced APP cleavage and upregulated genes associated with cholesterol transport and Aβ clearance (Yao et al., 2012). In other models with impaired autophagy-mediated clearance of Aβ, HP-β-CD normalized lysosomal function (Yang et al., 2017; Barbero-Camps et al., 2018). HP-β-CD itself sequestered Aβ in vitro, inhibiting peptide aggregation and toxicity (Ren et al., 2016).

In other preclinical work, HP-β-CD removed cholesterol from blood vessel plaques and promoted their regression in a mouse model of atherosclerosis (Zimmer et al., 2016).

Findings

Development of Trappsol® Cyclo™ in Niemann-Pick disease began with a compassionate use program in 12 children that supported its safety and potential benefit of intravenous treatment (Hastings et al., 2019). Cyclo Therapeutics subsequently conducted open-label Phase 1 and Phase 2 studies of up to 48 weeks treatment in children and adults. In these trials, the drug had mainly mild to moderate side effects, most notably hearing impairment and infusion reactions. In a 14-week Phase 1 study in 13 adults, two withdrew because of changes in hearing. The drug was detected in CSF, and changes in CSF tau and serum 14S-hydroxycholesterol were consistent with target engagement in the central nervous system (Hastings et al., 2022). A 48-week Phase 1/2 in 12 children yielded similar results, as well as stabilization or improvement in symptoms in the eight who completed the study (Jun 2021 company presentation).

In July 2021, the company began a Phase 3 trial enrolling 93 children and adults age 3 and older to receive 2,000 mg/kg or placebo, every two weeks for two years, against an endpoint of change from baseline in symptom severity at one and two years. This trial is being conducted at 13 sites in the U.S., Australia, Germany, Poland, Spain, Israel, and Turkey, through December 2023. It includes a two-year open-label extension to run through the end of 2025. The study also provides open-label treatment of 12 infants or toddlers younger than 3 years old in a preventive paradigm. 

Investigations for Alzheimer's disease began with an 18-month compassionate use trial in one patient with late-onset AD, who started on a 500 mg/kg monthly infusion. According to a company report, the drug was safe, and the patient’s disease did not progress. Improvements in agitation and word finding were reported (Jun 2020 press release).

In September 2022, a Phase 2 study began to test the drug in early Alzheimer’s disease. The study is enrolling 90 people, at five sites in the U.S., to receive six monthly infusions of 500 mg/kg, 1,000 mg/kg or placebo. The primary outcome is safety; secondaries include changes in standard cognitive and functional measures. The study will run through March 2024.

For details on Trappsol® Cyclo™ trials, see clinicaltrials.gov.

Last Updated: 19 Jan 2023

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References

Paper Citations

  1. Hastings C, Vieira C, Liu B, Bascon C, Gao C, Wang RY, Casey A, Hrynkow S. Expanded access with intravenous hydroxypropyl-β-cyclodextrin to treat children and young adults with Niemann-Pick disease type C1: a case report analysis. Orphanet J Rare Dis. 2019 Oct 21;14(1):228. PubMed.
  2. Hastings C, Liu B, Hurst B, Cox GF, Hrynkow S. 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 . Mol Genet Metab. 2022 Dec;137(4):309-319. Epub 2022 Oct 17 PubMed.
  3. Cronin S, Lin A, Thompson K, Hoenerhoff M, Duncan RK. Hearing Loss and Otopathology Following Systemic and Intracerebroventricular Delivery of 2-Hydroxypropyl-Beta-Cyclodextrin. J Assoc Res Otolaryngol. 2015 Oct;16(5):599-611. Epub 2015 Jun 9 PubMed.
  4. Scantlebery AM, Ochodnicky P, Kors L, Rampanelli E, Butter LM, El Boumashouli C, Claessen N, Teske GJ, van den Bergh Weerman MA, Leemans JC, Roelofs JJ, Florquin S. β-Cyclodextrin counteracts obesity in Western diet-fed mice but elicits a nephrotoxic effect. Sci Rep. 2019 Nov 27;9(1):17633. PubMed.
  5. Malnar M, Hecimovic S, Mattsson N, Zetterberg H. Bidirectional links between Alzheimer's disease and Niemann-Pick type C disease. Neurobiol Dis. 2014 Dec;72PA:37-47. Epub 2014 Jun 4 PubMed.
  6. Davidson CD, Ali NF, Micsenyi MC, Stephney G, Renault S, Dobrenis K, Ory DS, Vanier MT, Walkley SU. Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression. PLoS One. 2009 Sep 11;4(9):e6951. PubMed.
  7. Liu B, Ramirez CM, Miller AM, Repa JJ, Turley SD, Dietschy JM. Cyclodextrin overcomes the transport defect in nearly every organ of NPC1 mice leading to excretion of sequestered cholesterol as bile acid. J Lipid Res. 2010 May;51(5):933-44. Epub 2009 Nov 18 PubMed.
  8. Yao J, Ho D, Calingasan NY, Pipalia NH, Lin MT, Beal MF. Neuroprotection by cyclodextrin in cell and mouse models of Alzheimer disease. J Exp Med. 2012 Dec 17;209(13):2501-13. PubMed.
  9. Yang DS, Stavrides P, Kumar A, Jiang Y, Mohan PS, Ohno M, Dobrenis K, Davidson CD, Saito M, Pawlik M, Huo C, Walkley SU, Nixon RA. Cyclodextrin has conflicting actions on autophagy flux in vivo in brains of normal and Alzheimer model mice. Hum Mol Genet. 2017 Mar 1;26(5):843-859. PubMed.
  10. Barbero-Camps E, Roca-Agujetas V, Bartolessis I, de Dios C, Fernández-Checa JC, Marí M, Morales A, Hartmann T, Colell A. Cholesterol impairs autophagy-mediated clearance of amyloid beta while promoting its secretion. Autophagy. 2018;14(7):1129-1154. Epub 2018 Jun 4 PubMed.
  11. Ren B, Jiang B, Hu R, Zhang M, Chen H, Ma J, Sun Y, Jia L, Zheng J. HP-β-cyclodextrin as an inhibitor of amyloid-β aggregation and toxicity. Phys Chem Chem Phys. 2016 Jul 27;18(30):20476-85. PubMed.
  12. Zimmer S, Grebe A, Bakke SS, Bode N, Halvorsen B, Ulas T, Skjelland M, De Nardo D, Labzin LI, Kerksiek A, Hempel C, Heneka MT, Hawxhurst V, Fitzgerald ML, Trebicka J, Björkhem I, Gustafsson JÅ, Westerterp M, Tall AR, Wright SD, Espevik T, Schultze JL, Nickenig G, Lütjohann D, Latz E. Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming. Sci Transl Med. 2016 Apr 6;8(333):333ra50. PubMed.

External Citations

  1. company presentation
  2. press release
  3. clinicaltrials.gov

Further Reading

Papers

  1. Dudhipala N, Ettireddy S, Youssef AA, Puchchakayala G. Development and In vivo Pharmacokinetic and Pharmacodynamic Evaluation of an Oral Innovative Cyclodextrin Complexed Lipid Nanoparticles of Irbesartan Formulation for Enhanced Bioavailability. Nanotheranostics. 2023;7(1):117-127. PubMed.
  2. Du J, Liu X, Zhang Y, Han X, Ma C, Liu Y, Guan L, Qiao L, Lin J. The Effects of Combined Therapy With Metformin and Hydroxypropyl-β-Cyclodextrin in a Mouse Model of Niemann-Pick Disease Type C1. Front Pharmacol. 2021;12:825425. Epub 2022 Jan 14 PubMed.
  3. Yergey AL, Blank PS, Cologna SM, Backlund PS, Porter FD, Darling AJ. Characterization of hydroxypropyl-beta-cyclodextrins used in the treatment of Niemann-Pick Disease type C1. PLoS One. 2017;12(4):e0175478. Epub 2017 Apr 17 PubMed.
  4. Coisne C, Tilloy S, Monflier E, Wils D, Fenart L, Gosselet F. Cyclodextrins as Emerging Therapeutic Tools in the Treatment of Cholesterol-Associated Vascular and Neurodegenerative Diseases. Molecules. 2016 Dec 20;21(12) PubMed.
  5. Mattsson N, Olsson M, Gustavsson MK, Kosicek M, Malnar M, Månsson JE, Blomqvist M, Gobom J, Andreasson U, Brinkmalm G, Vite C, Hecimovic S, Hastings C, Blennow K, Zetterberg H, Portelius E. Amyloid-β metabolism in Niemann-Pick C disease models and patients. Metab Brain Dis. 2012 Dec;27(4):573-85. PubMed.
  6. Maulik M, Ghoshal B, Kim J, Wang Y, Yang J, Westaway D, Kar S. Mutant human APP exacerbates pathology in a mouse model of NPC and its reversal by a β-cyclodextrin. Hum Mol Genet. 2012 Nov 15;21(22):4857-75. PubMed.