Title:2-Hydroxypropyl-β-cyclodextrins and the Blood-Brain Barrier: Considerations for Niemann-Pick Disease Type C1
Volume: 23
Issue: 40
Author(s): Pericles Calias*
Affiliation:
- Co-Founder and Pharmaceutical Development Consultant, Educational Trainers and Consultants, 39 Swains Pond Ave, Melrose, MA 02176,United States
Keywords:
2-hydroxypropyl-β-cyclodextrins, blood-brain barrier, cyclodextrins, intraperitoneal, intrathecal, lysosomal storage disease, neurodegenerative,
Niemann-Pick disease type C, subcutaneous.
Abstract: The rare, chronic, autosomal-recessive lysosomal storage disease Niemann-Pick disease type C1
(NPC1) is characterized by progressively debilitating and ultimately fatal neurological manifestations. There is an
urgent need for disease-modifying therapies that address NPC1 neurological pathophysiology, and passage
through the blood-brain barrier represents an important consideration for novel NPC1 drugs. Animal investigations
of 2-hydroxypropyl-β-cyclodextrins (HPβCD) in NPC1 in mice demonstrated that HPβCD does not cross
the blood-brain barrier in significant amounts but suggested a potential for these complex oligosaccharides to
moderately impact CNS manifestations when administered subcutaneously or intraperitoneally at very high doses;
however, safety concerns regarding pulmonary toxicity were raised. Subsequent NPC1 investigations in cats
demonstrated far greater HPβCD efficacy at much lower doses when the drug was administered directly to the
CNS. Based on this, a phase 1/2a clinical trial was initiated with intrathecal administration of a specific, wellcharacterized
mixture of HPβCD, with a tightly controlled molar substitution specification and a defined molecular
“fingerprint” of the different species. The findings were very encouraging and a phase 2b/3 clinical trial has
completed enrollment and is underway. In addition, phase 1 clinical studies utilizing high-dose intravenous administration
of a different HPβCD are currently recruiting. Independent studies are needed for each product to
satisfactorily address questions of safety, efficacy, dosing, and route of administration. The outcomes cannot be
assumed to be translatable between HPβCD products and/or routes of administration.
