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.

Keywords: 2-hydroxypropyl-β-cyclodextrins, blood-brain barrier, cyclodextrins, intraperitoneal, intrathecal, lysosomal storage disease, neurodegenerative, Niemann-Pick disease type C, subcutaneous.