combined intrathecal and intravenous vts-270 therapy for liver and neurological disease associated with niemann-pick disease, type c1

Conditions: Niemann-Pick Disease, Type C1

Summary: background: for people who have niemann-pick disease, type c1 (npc1), cholesterol and other fats have trouble moving out of liver and other tissue cells. this makes the cells sick. researchers want to find out if a drug called vts-270 can help. objective: to test if vts-270 is safe and effective in treating chronic liver disease associated with npc1. eligibility: people ages 3-60 with npc1 design: participants may be screened by phone or under another protocol. participants will have visits once a month for 12 months. if they have intrathecal injections, the study may last 15 months or more. the first visit will last about 5 days. others will last 2-3 days. participants will get vts-270 injected into a vein at each visit. they can also choose to have intrathecal injections. these are like spinal taps. some visits will also include: physical exam urine tests blood tests. a small tube or needle will be inserted into the participants vein to collect blood. the small tube will also be used to give the vts-270. hearing tests: for one test, participants will have electrodes taped to their head. these will record brain waves. breathing tests ultrasound of abdomen: sounds waves will take pictures of the participant s body. chest x-ray: this is a picture of the lungs.

niemann-pick disease type c (npc) is a lethal, autosomal recessive, lysosomal storage disorder characterized by neurodegeneration in early childhood and death in adolescence. npc results from mutation of either the npc1 (approximately 95% of cases) or npc2 genes. biochemically, npc is characterized by the endolysosomal storage of unesterified cholesterol and lipids in both the central nervous system and peripheral tissues such as the liver. individuals with npc demonstrate progressive cerebellar ataxia and dementia. acute cholestatic liver disease is frequently observed in the neonatal/infantile period but subsequently resolves. however, chronic, sub-clinical liver disease persists. intrathecal 2-hydroxypropyl-beta-cyclodextrin (hpbetacd, vts-270) has proven effective in reducing signs and prolonging life in npc1 animal models, and phase 1/2a data support efficacy in npc1 patients. parenteral administration of vts-270 has also been shown to be effective in treating liver disease in the npc1 cat. in this phase 1/2a, open-label, randomized, parallel dose, single-center study, we will examine whether vts-270 can be used to treat chronic subacute liver disease in npc1 patients. our primary objective is to determine the safety and tolerability of intravenous vts-270 in npc1 disease. secondary objectives will be to evaluate the efficacy of vts-270 to reduce plasma cholestane-3beta,5alpha,6beta-triol, an npc1-specific pharmacodynamic biomarker, and to normalize the degree of liver injury. exploratory testing will include lipid and protein biomarkers. this study will evaluate three dose levels (500, 1000 and 1500 mg/kg) administered monthly for twelve months. safety will be assessed by adverse event recording, clinical laboratory testing and physical examination. clinical efficacy will be evaluated by assessment of liver chemistries, determination of liver size; and liver stiffness. biochemical efficacy will be assessed by measurement of plasma cholestane-3beta,5alpha,6beta-triol and other biomarkers.

Eligibility criteria:
-inclusion criteria: 1. age greater than or equal to 3 and less than or equal to 60 years old at time of enrollment 2. diagnosis of npc1 based upon one of the following: a. two npc1 mutations b. biochemical positive for npc (oxysterol/bile acid and sphingomyelinase levels consistent with a diagnosis of npc) and one npc1 mutation * npc1 mutations will be interpreted using standards established for the interpretation of sequence variants \[33\]. * oxysterol/bile acid testing refers to cholestane-3beta,5 ,6beta-triol \[7, 8\] or 3beta,5alpha,6beta-trihydroxycholanic acid and its glycine conjugate \[34\]. 3. evidence of npc1-related liver disease as defined by one of the following: a. abnormal liver chemistries as defined by one of the following: i. plasma aspartate aminotransferase (ast) greater than or equal to 1.5-times age-appropriate upper limit of normal ii. plasma aspartate aminotransferase (ast) greater than or equal to 1.25-times age-appropriate upper limit of normal and plasma alanine aminotransferase (alt) \> 1.25-times age-appropriate upper limit of normal iii. plasma aspartate aminotransferase (ast) greater than or equal to 1.25-times age-appropriate upper limit of normal and ast/alt ratio greater than or equal to 2.0 and abnormal liver chemistries as defined above at least 8 weeks apart. b. abnormal liver ultrasound\* defined as one of the following: 1. intraparenchymal echogenic bands consistent with fibrosis 2. abnormal liver echogenicity with ast or alt above the upper limit of normal. 3. hepatomegaly with ast or alt above the upper limit of normal. to define hepatomegaly, we will use the suggested limit of normal of the longitudinal dimension of the right lobe of the liver. these values are approximately 2 standard deviations above the mean. c. abnormal liver stiffness (fibroscan\*\*) for age. to define liver stiffness measurement we will use the normal age dependent ranges. values above the 95th centile will be considered abnormal. 4. ability to travel to the nih clinical center repeatedly for evaluation and follow-up. 5. willingness to discontinue all non-prescription supplements, except for an age-appropriate multivitamin/mineral supplement. 6. stable miglustat dose for 3 months prior to entry into the iv portion of the trial. 7. women of reproductive age must be willing to use an effective method of contraception for the duration of the trial if sexually active. 8. willingness to participate in all aspects of the iv trial exclusion criteria: * age \ 60 years of age at time of enrollment in the trial. * subjects who have received any form of parenteral cyclodextrin, an hdac inhibitor, or an experimental therapy for npc in the prior six months. prior intrathecal vts-270 treatment is allowed. * history of hypersensitivity reactions to cyclodextrin or components of the formulation. * pregnancy or breastfeeding. females of childbearing potential unwilling to utilize a highly effective form of contraception (i.e., barrier method with spermicide, intrauterine device, steroidal contraceptive in conjunction with a barrier method, or abstinence if it is the patient s baseline preference) for the duration of the study and for 30 days after participation. * any systemic infection at the time of enrollment. * neutropenia, defined as an absolute neutrophil count (anc) of less than 1,500 per microliter. subjects with benign cyclic/ethnic neutropenia may be enrolled if not clinically symptomatic. * thrombocytopenia defined as a platelet count less than 75,000 per microliter. * established history of a chronic clotting or bleeding disorder. * use of anticoagulants within 3 months of enrollment * severe or acute liver disease as defined by one of the following: a. ast or alt greater than 10-times age-appropriate upper limit of normal b. jaundice or right upper quadrant pain c. international normalized ratio (inr) \>1.8 * individuals with ast and alt greater than 4-times the age-appropriate upper limit of normal will be excluded if they have a positive nih clinical center viral markers hepatitis screen (hbsag, anti-hcv and anti-hav igm). this screening test will not be obtained unless ast and alt are elevated. an equivalent panel from another laboratory may be used if this elevation is noted on screening. individuals excluded under this criterion may be rescreened after the acute pathology resolves (e.g. hepatitis a infection). * presence of anemia defined as two standard deviations below normal for age and gender. * serum creatinine level greater than 1.5 times the age-appropriate upper limit of normal or for individuals \>= 6 years of age an egrf \< 60 ml/min 1.73 m squared * hematuria on a single urinalysis, as defined by the american urological association (aua) as five or more red blood cells per high-power field on microscopic evaluation of urinary sediment from a properly collected urinalysis specimen. the patient will not be excluded if two subsequent urine specimens are negative for hematuria as defined by the aua. * proteinuria (1+ protein on repeat urinalysis) unless evaluated and classified as benign. * active pulmonary disease, oxygen requirement or clinically significant history of decreased blood oxygen saturation (sao2 \<95% on room air), pulmonary therapy, daily use of a cough assist device or pulmonary vest, requiring active suction, or with a tracheostomy. * patients with uncontrolled seizures per either of the criteria below. 1. unstable frequency, type or duration of seizures. quantified by a seizure log over one month prior to enrollment. 2. subject requiring antiepileptic medication changes (other than dose adjustments for weight) in the month prior to enrollment. * individuals receiving parenteral nutrition will be excluded. * patients, who in the opinion of the investigators, are unable to comply with the protocol or have specific health concerns that would potentially increase the risk of participation. additional exclusion criteria for intrathecal vts-270 1. neurologically asymptomatic. determination made by the investigators based on history, neurological exam and consultant input. 2. suspected infection of the central nervous system 3. spinal deformity that would impact the ability to perform a lumbar puncture 4. skin infection in the lumbar region 5. prior use of anticoagulants or a bleeding disorder with increased risk of clinical bleeding. 6. patients unable to complete a behavioral audiological evaluation including pure-tone threshold assessment (500 hz to 8000 hz). in consultation with the medical monitor and audiologists, a sedated abr may be utilized to monitor ototoxicity if the participant is being sedated to receive it vts-270. 7. patients, who in the opinion of the investigators, are unable to comply with the protocol or have specific health concerns that would potentially increase the risk of participation.

Keywords: 2-hydroxypropyl-b-cyclodextrin