Alpha-1 antitrypsin treatment of new-onset type 1 diabetes: An open-label, phase I clinical trial (RETAIN) to assess safety and pharmacokinetics

Abstract

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 NP (AAT). This open-label, dose-escalation study enrolled 8 adults aged 16 to 35 years and 8 children aged 8 to 15 years within 100 days of diagnosis, to receive 12 infusions of AAT: a low dose of 45 mg/kg weekly for 6 weeks, followed by a higher dose of 90 mg/kg for 6 weeks.

Results: C-peptide secretion during a mixed meal, hemoglobin A1c (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 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. Polymerase chain reaction (PCR) analyses were performed on inhibitor of IKBKE, NOD1, TLR1, and TRAD gene expression, which are important for activation of nuclear factor-κB (NF-κB) and apoptosis pathways. AAT suppressed expression dose-dependently; 50% inhibition was achieved in the 2.5 to 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.

Keywords: C-peptide; autoimmune diseases; diabetes mellitus; pharmacokinetics; serine proteinase inhibitors; type 1 diabetes.

© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Figures

Figure 1

The means of C-peptide 2-hour AUC, HbA1c and insulin use (units per kg per day) over 730 days. A. C. & E. Adult cohort. B, D & F. Pediatric cohort. The means of the adult and pediatric cohorts are indicated by dotted lines, respectively. C-peptide mean 2-hour AUC is calculated as the area under the curve of C-peptide from 2-hour mixed meal tolerance test divided by the duration of test (120 minutes).

Figure 2

Dose response of AAT on fresh blood. Data are mean +/− SD from 9 Adult subjects with type 1 diabetes (normalized to HK genes + no AAT). Associations between No AAT and different concentrations of AAT are tested using Paired t-test and a p-value <0.05 determined statistical significance. *p<0.05, **p<0.005

Figure 3

Observed plasma AAT concentrations at each infusion visit and projected lower 95% confidence limits of plasma AAT blood concentrations at various dose levels by cohort. Panels A, B, C, and D show mean plasma AAT concentrations (solid line indicates first dose and dashed line indicates final dose). Note: Reference lines at 2.0 and 2.5 indicate the target range of concentration levels at 120 hours post infusion. There were six infusions at the low dose (45 mg/kg/wk) and six infusions at the high dose (90 mg/kg/wk). A. Adult cohort, low dose. B. Pediatric cohort, low dose. C. Adult cohort, high dose. D. Pediatric cohort, high dose. Panels E and F projections are based on the assumption of dose proportionality and a constant baseline plasma AAT concentration over time. Concentration levels after the last high dose infusion are used as bases for the projection. E. Adult cohort. F. Pediatric cohort. Projected dose (mg/kg) 90 (triangle), 180 (square), and 270 (circle).