Hydroxypropyl Beta Cyclodextrin for Niemann-Pick Type C1 Disease

Niemann-Pick disease type C (NPC) is a lethal, autosomal recessive, lysosomal storage disorder characterized by neurodegeneration in early childhood and death in adolescence. The causative genes NPC1 (about 95% of cases) and NPC2 (about 5% of cases) are involved in the intracellular trafficking of lipids and cholesterol. Mutations on either of these genes lead to progressive accumulation of unesterified cholesterol and other lipids in the central nervous system (CNS). The National Institutes of Health (NIH) Therapeutics for Rare and Neglected Diseases (TRND) program is developing 2-hydroxypropyl-Beta-cyclodextrin (HP-Beta-CD) for the treatment of patients with Niemann-Pick disease type C1 (NPC1) to slow progression of symptoms of the disease. In this Phase 1, non-randomized, open-label, single-center, study, we propose to administer HP-Beta-CD intrathecally via lumbar injection to drug naive cohorts of 3 patients at doses of 200 mg escalated to 300, 400 mg and 900 mg. Subsequent dose escalations may occur in increments of up to 300 mg. The objectives of this study are to assess the safety, tolerability, feasibility, and pharmacokinetics (PK) of intrathecally (IT) administered HP-Beta-CD to NPC1 patients, to determine an active dose of HP-Beta-CD as measured by changes in plasma 24-(S) hydroxycholesterol (24(S)-HC) concentration, and to evaluate the use of biomarkers and potential clinical outcomes of NPC1. All patients in the cohort will receive HP-Beta-CD (n = 3) once monthly for at least two doses, and the decision to dose-escalate will be based on safety and on biochemical data. Safety will be assessed by adverse events (AEs), audiologic evaluation, clinical laboratory tests, vital signs, physical examinations, chest X-rays and electrocardiograms (ECGs). Biochemical efficacy will be measured by change from baseline in plasma 24(S)-HC. PK will be assessed for plasma HP-Beta-CD.