Intrathecal 2-hydroxypropyl-beta-cyclodextrin in a single patient with Niemann–Pick C1

Abstract

Niemann-Pick C, Type 1 (NPC1) is a progressive autosomal recessive neurologic disease caused by defective intracellular cholesterol and lipid trafficking. There are currently no United States Food and Drug Administration approved treatments for NPC1. We undertook a study evaluating the safety, efficacy, and biomarker response of intrathecal 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) in a 12-year old subject with mildly symptomatic NPC. The subject received 200mg intrathecal HP-β-CD administered biweekly via lumbar puncture. To date the subject has received 27 intrathecal HP-β-CD injections. Intrathecal HP-β-CD has been generally safe and well tolerated in this subject. There has been improvement in vertical gaze. The subject has developed subclinical hearing loss at high frequency that is likely HP-β-CD related. Plasma 24-(S)-hydroxycholesterol, a pharmacodynamic biomarker for cholesterol redistribution in the central nervous system, was significantly increased in response to each of the first 5 drug administrations. Further dosing as well as dose escalations are needed to more completely ascertain the safety and efficacy of intrathecal HP-β-CD.

Use of 2-Hydroxypropyl-Beta-Cyclodextrin for Niemann-Pick Type C Disease

“…This study also reported an increase in 24-OH cholesterol, a biomarker of cholesterol redistribution in CNS. On the other hand, an AE was associated to HP-β-CD administration, the well-known hearing loss to high frequency [44].…”

“…Of the 17 AEs reported, 6 were related to the route of administration, specifically with the IT and ICV routes and 10 of them could be attributed by HP-β-CD. Six AEs associated to the route were: CNS bleed related to insertion of the Ommaya reservoir system in a patient treated with ICV HP-β-CD led to ICV administration suspended [34]; post lumbar puncture headache and vomiting resolved with switching a Whitacre spinal needles [41][42][43]; post lumbar puncture pain, headache, nausea, and vomiting resolved with symptomatic and postural treatment [44]; seizures with fever resolved without changes in treatment [40] and aspiration pneumonia; febrile syndrome; and candidiasis resolved with antibiotic and antifungal treatment [49].…”

“…Among AEs related to HP-β-CD itself, loss of hearing was reported in four reported cases of IT infusions [41][42][43][44][45], although it proved reversible in two of them. These patients were administered with reduced doses of HP-β-CD after hearing recovery, two times in one of them.…”

Potential Use of Cyclodextrins as Drug Carriers and Active Pharmaceutical Ingredients

“…Recently, intrathecal infusion of HP-β-CyD to NPC patients has been performed to reduce the risk of adverse events in lung. 54) Meanwhile, Kondo et al 55) reported effects of hydroxyalkylated β-CyDs with different cholesterol-solubilizing abilities, such as 2-hydroxyethyl-β-CyD (HE-β-CyD) and 2-hydroxybutyl-β-CyD (HB-β-CyD). Based on the results regarding cholesterol solubilizing potential, attenuating the effects against NPC abnormalities and cytotoxicity induction, HB-β-CyD may be superior in terms of safety and efficacy in Npc1 null cells compared with HE-β-CyD and HB-β-CyD.…”

Diagnostic workup and management of patients with suspected Niemann-Pick type C disease

“…Intravenous HPBCD was trialled on two NP-C patients [Matsuo et al 2013] and had little or no effect in controlling or delaying neurological symptoms, although it resulted in improvement of liver size and function. A 12-year old patient with NPC1 was recently given HPBCD intrathecally every 2 weeks and response was assessed after 27 injections [Maarup et al 2015]. The NP-C severity scale score improved over 18 months, with all neurological functions remaining stable and a 1-point improvement shown in eye movements.…”