PMID- 37670901 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230907 IS - 2214-4269 (Print) IS - 2214-4269 (Electronic) IS - 2214-4269 (Linking) VI - 36 DP - 2023 Sep TI - Long-term administration of intravenous Trappsol(R) Cyclo (HP-beta-CD) 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. PG - 100988 LID - 10.1016/j.ymgmr.2023.100988 [doi] LID - 100988 AB - BACKGROUND: Niemann-Pick disease type C (NPC) is a rare, fatal, pan-ethnic, autosomal recessive lysosomal storage disease characterized by progressive major organ failure and neurodegeneration. Preclinical studies confirmed a critical role of systemically administered hydroxypropyl-beta-cyclodextrin (HP-beta-CD; Trappsol(R) Cyclo) in cholesterol metabolism and homeostasis in peripheral tissues of the body, including the liver, and in the central nervous system (CNS). Herein, the pharmacokinetics (PK), safety, and efficacy of HP-beta-CD, and biomarkers of NPC were assessed in pediatric and adult patients with NPC1. METHODS: This was a multicenter, Phase I/II, randomized, double-blind, parallel-group, 48-week study (ClinicalTrials.gov identifier NCT02912793) to compare the PK of three different single intravenous (IV) doses of HP-beta-CD in pediatric and adult patients with NPC1 and to evaluate the efficacy and tolerability of three different dosages of HP-beta-CD in patients with NPC1 after long-term treatment. Twelve patients aged at least 2 years (2-39 years of age) with a confirmed diagnosis of NPC1 were randomized to receive one of three IV doses of HP-beta-CD (1500 mg/kg, 2000 mg/kg, or 2500 mg/kg) every 2 weeks for 48 weeks. All patients received HP-beta-CD; there was no placebo or other control. PK testing of plasma and cerebrospinal fluid (CSF) was at set times after the first infusion. Pharmacodynamic assessments included biomarkers of cholesterol metabolism (synthesis and breakdown products), N-palmitoyl-O-phosphocholineserine (PPCS), and specific biomarkers of CSF neurodegeneration (including total Tau), CNS inflammation (glial fibrillary acidic protein [GFAP] and tumor necrosis factor alpha [TNFalpha]), CNS cholesterol metabolism (24S-hydroxycholesterol) and inflammatory markers. Efficacy measures included clinical disease severity, neurologic symptoms, and clinical impressions of improvement. Safety assessment included physical examination, vital signs, clinical safety laboratory assessment and adverse events (AEs). RESULTS: Nine patients completed the study, 2 in the 1500 mg/kg group, 4 in the 2000 mg/kg group and 3 in the 2500 mg/kg group. Three patients (all in the 1500 mg/kg group) discontinued the study because of either physician decision/site Principal Investigator (PI) discretion, withdrawal by subject/patient/parent/guardian, or other non-safety reasons. In 5 patients who underwent serial lumbar punctures, HP-beta-CD was detected in the CSF. Of the 9 patients who completed the study, 8 (88.9%) improved in at least two domains of the 17-Domain Niemann-Pick disease Type C-Clinical Severity Scale (17D-NPC-CSS), and 6 of these patients improved in at least one domain viewed by patients and their caregivers to be key to quality of life, namely, speech, swallow, fine and gross motor skills, and cognition. Of the 9 patients who completed the study, 7 were viewed by their treating physicians as having improved to some degree at the end of the study, and 2 remained stable; both outcomes are highly relevant in a progressive neurodegenerative disease. Some patients and families reported improvement in quality of life.All three doses of HP-beta-CD were well tolerated overall, with most treatment-emergent adverse events transient, mild-to-moderate in nature, and considered by the site PIs to be not related to study drug. INTERPRETATION: This 48-week trial is the longest to date to evaluate the safety, tolerability, and efficacy across multiple clinical endpoints of IV administration of Trappsol(R) Cyclo (HP-beta-CD) in NPC1 patients. In pediatric and adult patients with NPC, Trappsol(R) Cyclo IV improved clinical signs and symptoms and was generally well tolerated. The findings presented here demonstrate a favorable benefit-risk profile and support the global pivotal trial now underway to evaluate the long-term treatment benefits and the potential of Trappsol(R) Cyclo as a disease-modifying treatment in this patient population. CI - (c) 2023 The Author(s). FAU - Sharma, Reena AU - Sharma R AD - Salford Royal Hospital NHS Foundation Trust, Department of Adult Inherited Metabolic Diseases, Stott Lane, Salford, Greater Manchester M6 8HD, UK. FAU - Hastings, Caroline AU - Hastings C AD - UCSF Benioff Children's Hospital, Oakland, CA 94609, USA. FAU - Staretz-Chacham, Orna AU - Staretz-Chacham O AD - Soroka Medical Center, Rager Blvd, P.O.B. 151, Beer Sheva 84101, Israel. FAU - Raiman, Julian AU - Raiman J AD - Birmingham Children's Hospital, Steelhouse Lane, Birmingham B4 6NH, UK. FAU - Paucar, Martin AU - Paucar M AD - Karolinska University Hospital, Huddinge, Department of Neurology, R43 Rehabgatan, 4th Floor, 141 86 Stockholm, Sweden. FAU - Spiegel, Ronen AU - Spiegel R AD - Department of Pediatrics B, Emek Medical Center, Afula 1834111, Israel. AD - The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel. FAU - Murray, Bryan AU - Murray B AD - Boyd Consultants Ltd, Electra House, Crewe Business Park, Crewe, Cheshire CW1 6GL, UK. FAU - Hurst, Bryan AU - Hurst B AD - Boyd Consultants Ltd, Electra House, Crewe Business Park, Crewe, Cheshire CW1 6GL, UK. FAU - Liu, Benny AU - Liu B AD - Highland Hospital, 1411 East 31st Street, Oakland, CA 94602, USA. FAU - Kjems, Lise AU - Kjems L AD - Cyclo Therapeutics, Inc, 6714 NW 16th Street, Suite B, Gainesville, FL 32653, USA. FAU - Hrynkow, Sharon AU - Hrynkow S AD - Cyclo Therapeutics, Inc, 6714 NW 16th Street, Suite B, Gainesville, FL 32653, USA. LA - eng SI - ClinicalTrials.gov/NCT02912793 PT - Journal Article DEP - 20230629 PL - United States TA - Mol Genet Metab Rep JT - Molecular genetics and metabolism reports JID - 101624422 PMC - PMC10475848 OTO - NOTNLM OT - Biomarker OT - Cholesterol homeostasis OT - Cyclodextrin OT - Disease stabilization OT - NPC clinical severity scale OT - Niemann-Pick disease type C COIS- None. EDAT- 2023/09/06 06:42 MHDA- 2023/09/06 06:43 PMCR- 2023/06/29 CRDT- 2023/09/06 03:47 PHST- 2023/04/27 00:00 [received] PHST- 2023/06/21 00:00 [accepted] PHST- 2023/09/06 06:43 [medline] PHST- 2023/09/06 06:42 [pubmed] PHST- 2023/09/06 03:47 [entrez] PHST- 2023/06/29 00:00 [pmc-release] AID - S2214-4269(23)00034-4 [pii] AID - 100988 [pii] AID - 10.1016/j.ymgmr.2023.100988 [doi] PST - epublish SO - Mol Genet Metab Rep. 2023 Jun 29;36:100988. doi: 10.1016/j.ymgmr.2023.100988. eCollection 2023 Sep.