A Phase II, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study Evaluating the Efficacy and Safety of Alpha-1 Antitrypsin (AAT) (Glassia®) in the Treatment of Recent-Onset Type 1 Diabetes

Abstract

Our aim was to assess the efficacy, safety, and tolerability of alpha-1 antitrypsin (AAT) as a therapeutic modality for β-cell preservation in patients with recent-onset type 1 diabetes. Seventy type 1 diabetes patients (37 males; mean age 13.1 ± 4.1years) were randomized to treatment with 22 infusions of AAT (Glassia®) (60 or 120 mg/kg) or placebo. The primary outcome was the area under the curve (AUC) of C-peptide from a 2-h mixed-meal tolerance test after 52 weeks. At week 52, C-peptide was 0.9, 0.45, and 0.48 pmol/mL in the AAT-120, AAT-60, and placebo groups (p = 0.170 and p = 0.866 vs. placebo, respectively). The declines in C-peptide glycated hemoglobin (HbA1c) and the total insulin dose (U/kg) were similar across groups. Within the predefined 12–18-years subgroup, the C-peptide AUC decreased significantly in the placebo and AAT-60 groups (−0.34 and −0.54 pmol/mL, respectively, p < 0.01), with a borderline decrease in the AAT-120 group (−0.29 pmol/mL, p = 0.047). The mean HbA1c level was significantly lower in the AAT-120 group compared to the placebo (6.7% ± 0.9% vs. 8.2 ± 1.4%, p = 0.05), and a higher percentage of patients attained HbA1c ≤ 7% (75% vs. 25%, p = 0.05). AAT was tolerated well, with a similar safety profile between groups. The AAT intervention showed promise in the subgroup of adolescents with recent-onset type 1 diabetes. Further studies are warranted to determine the impact and proposed mechanism of action of AAT in β-cell preservation.

Accelerated Wound Border Closure Using a Microemulsion Containing Non-Inhibitory Recombinant α1-Antitrypsin

“…At the molecular level, the finding of more protease-dependent and independent aspects of hAAT joins a long list of dogma-defying studies where the role of protease inhibition in human pathologies might be overemphasized. Finally, the remarkable safety record of repeated infused clinical-grade hAAT for individuals as young as 4 years old [39][40][41], renders the molecule an attractive candidate for promoting wound healing, including via a topical microemulsion preparation.…”

A mutant α1antitrypsin in complex with heat shock proteins as the primary antigen in type 1 diabetes in silico investigation

“…Special focus has been placed on α1–antitrypsin (A1AT), the main circulating anti-proteinase inhibitor, which is used as a diabetes therapeutic agent for its broad anti-inflammatory and immune-modulatory properties unrelated to the specific proteinase inhibitory activity 7 . Although clinical trials of A1AT have not been successful 8 , the finding that A1AT is expressed in both islet 9 and endothelial cells 10 of the human pancreas, in addition to its protective effects on beta cells 11 , 12 and islet transplantation 13 , corroborated the idea that A1AT actually plays a role in regulating islet cell homeostasis and glucose metabolism, confirmed by studies on genes related to the metabolic syndrome 14 .…”

The Role of Proteases and Serpin Protease Inhibitors in β-Cell Biology and Diabetes

“…The abovementioned effects, along with a high safety profile that is associated with multiple intravenous doses of AAT in humans [ 45 ], provided the rationale to design and execute a randomized double-blind study in children with recent onset T1D. Although this intervention trial failed to demonstrate a significant positive impact on blood glucose control and residual β-cell function, a subgroup analysis revealed certain benefits in adolescent patients receiving the high dosage of AAT (120 mg/kg) [ 46 ].…”