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

Hastings, Caroline; Liu, Benny; Hurst, Bryan; Cox, Gerald F.; Hrynkow, Sharon

doi:10.1016/j.ymgme.2022.10.004

Cited by 24 publications

(22 citation statements)

References 52 publications

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“…Clinical testing of i.v. HP-β-CD for the chronic treatment of Niemann–Pick disease type C has reported cases of audiometrically detected high-frequency hearing loss with repeated doses of 1500 to 2500 mg kg −1 23 . There is no experience with NPJ5008 at these levels, and this dose level is not expected to be used in the treatment of malignant hyperthermia.…”

Section: Discussionmentioning

confidence: 99%

“…HP-β-CD for the chronic treatment of Niemann–Pick disease type C has reported cases of audiometrically detected high-frequency hearing loss with repeated doses of 1500 to 2500 mg kg −1 . 23 There is no experience with NPJ5008 at these levels, and this dose level is not expected to be used in the treatment of malignant hyperthermia. The relevance to the acute use of NPJ5008 in malignant hyperthermia is unclear; therefore, ototoxicity is not considered a substantial safety risk.…”

Section: Discussionmentioning

confidence: 99%

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The novel rapid formulation of intravenous dantrolene (NPJ5008) versus standard dantrolene (Dantrium®)

Ng Kwet Shing,

Clayton,

Smith

et al. 2024

European Journal of Anaesthesiology

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BACKGROUND Delays in treating anaesthesia-induced malignant hyperthermia increase risks of complications and death. NPJ5008 is a novel formulation of the indicated treatment, dantrolene sodium, developed to shorten preparation and administration times compared with the reference formulation DANTRIUM IV. The two formulations have been compared preclinically. OBJECTIVES Assess bioequivalence of overall dantrolene (free acid) exposure of NPJ5008 versus DANTRIUM IV and ascertain similarities in their pharmacokinetics and safety/tolerability profiles. Evaluate preparation/administration time savings for the new formulation. DESIGN Part 1 of this open-label trial in humans was a 1 : 1 randomised crossover study; part 2 was a single-arm study. Trial pharmacy data and laboratory simulations assessed preparation/administration step timings. SETTING Single clinical centre in the UK, April to July 2021. PARTICIPANTS Twenty-one healthy male and female individuals. INTERVENTIONS Part 1: single intravenous 60 mg dose of NPJ5008 or DANTRIUM IV, sequentially. Part 2: single intravenous 120 mg dose of NPJ5008. Simulation: five vials per formulation using paediatric and adult cannulas. MAIN OUTCOME MEASURES Overall drug exposure to last measurable concentration (AUC0 to last) and extrapolated to infinity (AUC0 to ∞) were primary endpoints. Other pharmacokinetic, clinical and muscle-function parameters, and adverse events, were monitored. RESULTS Adjusted geometric mean ratios of NPJ5008 versus DANTRIUM IV were 90.24 and 90.44% for AUC0 to last and AUC0 to ∞, respectively, with the 90% confidence intervals (CI) within the 80 to 125% acceptance interval, establishing bioequivalence. No new safety issues emerged: any adverse events were of a similar magnitude across treatments and related to pharmacological properties of dantrolene. Pharmacy and simulation data revealed that every step in preparation and administration was 26 to 69% faster for NPJ5008 than DANTRIUM IV. CONCLUSION NPJ5008 showed comparable pharmacokinetic and safety profiles to DANTRIUM IV, while reducing dantrolene dose preparation/administration times, potentially reducing patient complications/healthcare resourcing in malignant hyperthermia. TRIAL REGISTRATION EudraCT Number: 2020-005719-35, MHRA approval.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The novel rapid formulation of intravenous dantrolene (NPJ5008) versus standard dantrolene (Dantrium®)

Ng Kwet Shing,

Clayton,

Smith

et al. 2024

European Journal of Anaesthesiology

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“…Statins reduce overall cholesterol biosynthesis and have anti-inflammatory properties, in part because of decreasing the cholesterol inflow supporting lipid rafts in macrophages [31]. β-Cyclodextrins, which effectively sequester cholesterol, have been used in many in-vitro and in-vivo studies and in clinical trials to treat Niemann–Pick disease [28 ▪▪ ,32,33]. LXR agonists and reconstituted HDL or apoA-I mimetics facilitate cholesterol efflux and thus the reduction of lipid rafts [34 ▪▪ ,35].…”

Section: Inflammarafts As a Therapeutic Targetmentioning

confidence: 99%

Macrophage inflammarafts in atherosclerosis

Li,

Navia-Pelaez,

Choi

et al. 2023

Current Opinion in Lipidology

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Purpose of review Advances in single cell techniques revealed a remarkable diversity in macrophage gene expression profiles in atherosclerosis. However, the diversity of functional processes at the macrophage plasma membrane remains less studied. This review summarizes recent advances in characterization of lipid rafts, where inflammatory receptors assemble, in macrophages that undergo reprogramming in atherosclerotic lesions and in vitro under conditions relevant to the development of atherosclerosis. Recent findings The term inflammarafts refers to enlarged lipid rafts with increased cholesterol content, hosting components of inflammatory receptor complexes assembled in close proximity, including TLR4-TLR4, TLR2-TLR1 and TLR2-CD36 dimers. Macrophages decorated with inflammarafts maintain chronic inflammatory gene expression and are primed to an augmented response to additional inflammatory stimuli. In mouse atherosclerotic lesions, inflammarafts are expressed primarily in nonfoamy macrophages and less in lipid-laden foam cells. This agrees with the reported suppression of inflammatory programs in foam cells. In contrast, nonfoamy macrophages expressing inflammarafts are the major inflammatory population in atherosclerotic lesions. Discussed are emerging reports that help understand formation and persistence of inflammarafts and the potential of inflammarafts as a novel therapeutic target. Summary Chronic maintenance of inflammarafts in nonfoamy macrophages serves as an effector mechanism of inflammatory macrophage reprogramming in atherosclerosis.

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“…Other substances are in development for NPC, such as chaperone-treatment with arimoclomol [ 92 ], AZ-3102 [ 79 ], efavirenz [ 93 ] or cyclodextrin [ 94 ], and are at different development stages. A phase 2, 12-week study evaluating the safety, tolerability, pharmacokinetics, and pharmacodynamics of oral AZ-3102 in patients with NPC or GM2 gangliosidosis (see above) has just been initiated (NCT05758922).…”

Section: Lysosomal Storage Diseasesmentioning

confidence: 99%

Inborn Errors of Metabolism with Ataxia: Current and Future Treatment Options

Bremova-Ertl,

Hofmann,

Stucki

et al. 2023

Cells

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A number of hereditary ataxias are caused by inborn errors of metabolism (IEM), most of which are highly heterogeneous in their clinical presentation. Prompt diagnosis is important because disease-specific therapies may be available. In this review, we offer a comprehensive overview of metabolic ataxias summarized by disease, highlighting novel clinical trials and emerging therapies with a particular emphasis on first-in-human gene therapies. We present disease-specific treatments if they exist and review the current evidence for symptomatic treatments of these highly heterogeneous diseases (where cerebellar ataxia is part of their phenotype) that aim to improve the disease burden and enhance quality of life. In general, a multimodal and holistic approach to the treatment of cerebellar ataxia, irrespective of etiology, is necessary to offer the best medical care. Physical therapy and speech and occupational therapy are obligatory. Genetic counseling is essential for making informed decisions about family planning.

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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

Cited by 24 publications

References 52 publications

The novel rapid formulation of intravenous dantrolene (NPJ5008) versus standard dantrolene (Dantrium®)

The novel rapid formulation of intravenous dantrolene (NPJ5008) versus standard dantrolene (Dantrium®)

Macrophage inflammarafts in atherosclerosis

Inborn Errors of Metabolism with Ataxia: Current and Future Treatment Options

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