Pediatric Diabetes

 Alpha-1 antitrypsin treatment of new-onset type 1 diabetes: an open-label, phase I clinical trial (RETAIN) to assess safety and pharmacokinetics
OBJECTIVE To determine the safety and pharmacokinetics of alpha-1 antitrypsin (AAT) in adults and children. RESEARCH DESIGN AND METHODS Short term AAT treatment restores euglycemia in the non-obese mouse model of type 1 diabetes. A phase I multicenter study in 16 subjects with new-onset type 1 diabetes studied the safety and pharmacokinetics of Aralast NPTM (AAT). This open-label, dose-escalation study enrolled eight adults ages 16-35 and eight children ages 8-15 within 100 days of diagnosis, to receive 12 infusions of AAT: a low dose of 45 mg/kg weekly for six weeks, followed by a higher dose of 90 mg/kg for six weeks. RESULTS C-peptide secretion during a mixed meal, HbA1c, and insulin usage remained relatively stable during the treatment period. At 72 hours after infusion of 90 mg/kg, mean levels of AAT fell below 2.0 g/L for 7 of 15 of the subjects. To identify a plasma level of AAT likely to be therapeutic, pharmacodynamic ex vivo assays were performed on fresh whole blood from adult subjects. PCR analyses were performed on inhibitor of IKBKE, NOD1, TLR1, and TRAD gene expression, which are important for activation of NF-?B and apoptosis pathways. AAT suppressed expression dose-dependently; 50% inhibition was achieved in the 2.5-5.0 mg/mL range. CONCLUSIONS AAT was well tolerated and safe in subjects with new-onset type 1 diabetes. Weekly doses of AAT greater than 90 mg/kg may be necessary for an optimal therapeutic effect.