Collaborative Development of 2-Hydroxypropyl-β-Cyclodextrin for the Treatment of Niemann-Pick Type C1 Disease

Abstract

In 2010, the National Institutes of Health (NIH) established the Therapeutics for Rare and Neglected Diseases (TRND) program within the National Center for Advancing Translational Science (NCATS), which was created to stimulate drug discovery and development for rare and neglected tropical diseases through a collaborative model between the NIH, academic scientists, nonprofit organizations, and pharmaceutical and biotechnology companies. This paper describes one of the first TRND programs, the development of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) for the treatment of Niemann-Pick disease type C1 (NPC1). NPC is a neurodegenerative, autosomal recessive rare disease caused by a mutation in either the NPC1 (about 95% of cases) or the NPC2 gene (about 5% of cases). These mutations affect the intracellular trafficking of cholesterol and other lipids, which leads to a progressive accumulation of unesterified cholesterol and glycosphingolipids in the CNS and visceral organs. Affected individuals typically exhibit ataxia, swallowing problems, seizures, and progressive impairment of motor and intellectual function in early childhood, and usually die in adolescence. There is no disease modifying therapy currently approved for NPC1 in the US. A collaborative drug development program has been established between TRND, public and private partners that has completed the pre-clinical development of HP-β-CD through IND filing for the current Phase I clinical trial that is underway. Here we discuss how this collaborative effort helped to overcome scientific, clinical and financial challenges facing the development of new drug treatments for rare and neglected diseases, and how it will incentivize the commercialization of HP-β-CD for the benefit of the NPC patient community.

Targeting cholesterol with β‐cyclodextrin sensitizes cancer cells for apoptosis

“…This is because there was a report that MBCD could induce apoptosis in human keratinocytes [16], while HPBCD does not have that effect [9]. Furthermore, when administered orally, absorption of HPBCD is better than that of MBCD [8].…”

“…Because our aim is to develop cancer combination therapies that include bCD, we were pleased to learn that when introduced into animal bodies, bCD attenuates the IGF1R-PI3K-AKT pathway at a dose well within the safety limit established by the clinical trial for HPBCD for the treatment of Niemann-Pick disease [9]. On the other hand, bCD may not be retained in circulation at high enough doses to be effective for sufficient time.…”

Development and validation of sensitive LC-MS/MS assays for quantification of HP-#x03B2;-CD in human plasma and CSF

“…Treatment with HP-␤ -CD ameliorates cholesterol storage, signifi cantly reducing neurodegeneration and increasing lifespan in murine and feline models of NPC1 disease (3)(4)(5)(6)(7). Based on these studies, individual use investigational new drug applications for HP-␤ -CD have been allowed for eight pediatric patients in the US, and a phase 1 trial for delivery of HP-␤ -CD directly into the lateral ventricle of NPC1 patients was initiated in January 2013 at the National Institutes of Health (NIH) ( 8 ). To support the clinical trial, a reliable assay capable of quantifying HP-␤ -CD in human plasma and cerebrospinal fl uid (CSF) was essential.…”

Identification of novel bile acids as biomarkers for the early diagnosis of Niemann‐Pick C disease

“…Other treatments for NPC are currently undergoing clinical trials (2‐hydroxypropyl‐β‐cyclodextrin 25, histone deacetylase inhibitors 26 and arimoclomol).…”