CLINICAL TRIAL: RHASM IN ADULTS WITH ACID SPHINGOMYELINASE DEFICIENCY

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a Phase 1, single-center, single-dose, dose escalation study to evaluate the safety, pharmacokinetics and pharmacodynamics of recombinant human acid sphingomyelinase (rhASM) in adults with Niemann Pick disease (NPD) due to ASM deficiency. For each patient, study participation will consist of a screening/baseline evaluation and enrollment phase; a 72-hr in-patient stay during which a single-dose infusion of rhASM will be administered; and a 2842-day post-treatment assessment phase with follow-up assessments at 14 and 28 days post-infusion and a 42-day follow-up phone call. A minimum of 15 eligible adult (age 18 to 65 years, inclusive) patients will be enrolled into the study. Patients will be stratified by the degree of splenomegaly in multiples of normal (MN), as an indicator of disease severity. Five ascending single-dose groups, consisting of a minimum of 3 patients each, will be evaluated for safety, PK and PD. The single doses of rhASM selected for this study are 0.03, 0.1 0.3, 0.6 and 1.0 mg/kg. Dose escalation will proceed sequentially from lowest to highest dose. All patients will be monitored on an in-patient basis for 72 hr following the infusion of rhASM, return for assessments on Days 14 and 28 and receive a follow-up phone call on Day 42. Safety monitoring over the 72-hr in-patient visit will include: adverse event (AE) reporting, physical examinations, vital signs (including continuous monitoring of heart rate), clinical laboratory evaluations (serum chemistries, hematology, coagulation studies, urinalysis), liver function tests (LFTs), and cytokines. In addition, pulmonary function testing (PFT), adrenal hormone levels (diurnal and post-adrenocorticotropic hormone (ACTH) stimulation testing for aldosterone, cortisol, and delta-4-androstenedione levels), fasting lipid profile (FLP), immunogenicity testing, chest X-Rays, electrocardiograms (ECG), echocardiograms (ECHO), liver biopsies, and magnetic resonance imaging (MRI) of the spleen and liver will be performed at selected time points pre- and post-infusion. Hypothesis: Ascending doses of rhASM administered as a single dose to adults with ASMD will be tolerated.