ABSTRACT
BACKGROUND: Niemann-Pick Disease Type C (NPC) is an inherited, often fatal neurovisceral lysosomal storage disease characterized by cholesterol accumulation in every cell with few known treatments. Defects in cholesterol transport cause sequestration of unesterified cholesterol within the endolysosomal system. The discovery that systemic administration of hydroxypropyl-beta cyclodextrin (HPßPD) to NPC mice could release trapped cholesterol from lysosomes, normalize cholesterol levels in the liver, and prolong life, led to expanded access use in NPC patients. HPßCD has been administered to NPC patients with approved INDs globally since 2009. RESULTS: Here we present safety, tolerability and efficacy data from 12 patients treated intravenously (IV) for over 7 years with HPßCD in the US and Brazil. Some patients subsequently received intrathecal (IT) treatment with HPßCD following on average 13 months of IV HPßCD. Several patients transitioned to an alternate HPßCD. Moderately affected NPC patients treated with HPßCD showed slowing of disease progression. Severely affected patients demonstrated periods of stability but eventually showed progression of disease. Neurologic and neurocognitive benefits were seen in most patients with IV alone, independent of the addition of IT administration. Physicians and caregivers reported improvements in quality of life for the patients on IV therapy. There were no safety issues, and the drug was well tolerated and easy to administer. CONCLUSIONS: These expanded access data support the safety and potential benefit of systemic IV administration of HPßCD and provide a platform for two clinical trials to study the effect of intravenous administration of HPßCD in NPC patients.