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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-?B (NF-?B) 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.

SUBMITTER: Weir GC

PROVIDER: S-EPMC6030471 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Weir Gordon C GC Ehlers Mario R MR Harris Kristina M KM Kanaparthi Sai S Long Alice A Phippard Deborah D Weiner Lia J LJ Jepson Brett B McNamara James G JG Koulmanda Maria M Strom Terry B TB

Pediatric diabetes 20180507 5

<h4>Objective</h4>To determine the safety and pharmacokinetics of alpha-1 antitrypsin (AAT) in adults and children.<h4>Research design and methods</h4>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 10 ...[more]

PMID: 29473705

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Project description:INTRODUCTION:The B cell survival factor B lymphocyte stimulator (BLyS) is elevated in patients with systemic lupus erythematosus (SLE) and associated with disease activity. Belimumab, a monoclonal antibody specific for soluble BLyS, is approved for the treatment of adults with active, autoantibody-positive SLE receiving standard therapy. Ethnicity is one of the factors that can potentially affect the pharmacokinetics (PK) of therapeutic monoclonal antibodies, and therefore their efficacy and safety. METHODS:This phase 1, open-label study (200909) evaluated the pharmacokinetics (PK, primary objective), pharmacodynamics (PD), and safety (secondary objectives) of belimumab in Chinese patients with SLE (N = 20). Blood samples were taken up to 84 days after a single intravenous (IV) dose of belimumab 10 mg/kg. RESULTS:Peak serum concentrations of belimumab (Cmax) were obtained within the 1-h infusion. Geometric mean Cmax, area under the concentration-time curve (time 0 to last quantifiable concentration), terminal half-life, systemic clearance, and volume of distribution were 221 μg/mL, 2395 day·μg/mL, 14.6 days, 4.06 mL/day/kg, and 85.7 mL/kg, respectively. Decreases in CD20+, CD20+/CD27- naïve, CD20+/CD69+ active, CD20+/CD138+ plasmacytoid, CD19+/CD27BRIGHT/CD38BRIGHT SLE subset, and CD20-/CD138+ plasma B Cells post-dose were accompanied by an increase in CD20+/CD27+ memory B cells. Four cases of upper respiratory tract infection (three mild, one moderate) and one case of mild pharyngitis were possibly drug-related; all resolved during the study. CONCLUSION:PK of a single belimumab 10 mg/kg IV dose in Chinese patients with SLE were similar to those observed previously in Japanese and American (white and African-American) patients with SLE. PD results were consistent with belimumab inhibiting BLyS, and belimumab was well tolerated. These data support the use of belimumab in Chinese patients with SLE. TRIAL REGISTRATION:ClinicalTrials.gov identifier, NCT02880852.

Project description:BackgroundThe introductions of anti- human epidermal growth factor receptor-2 (HER2) agents have significantly improved the treatment outcome of patients with HER2-positive breast cancer. BAT8001 is a novel antibody-drug conjugate targeting human epidermal growth factor receptor-2 (HER2)-expressing cells composed of a trastuzumab biosimilar linked to the drug-linker Batansine. This dose-escalation, phase I study was designed to assess the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of BAT8001 in patients with HER2-positive locally advanced or metastatic breast cancer.MethodsThis trial was conducted in subjects with histologically confirmed HER2-positive breast cancer (having evaluable lesions and an Eastern Cooperative Oncology Group performance status of 0 or 1) using a 3?+?3 design of escalating BAT8001 doses. Patients received BAT8001 intravenously in a 21-day cycle, with dose escalation in 5 cohorts: 1.2, 2.4, 3.6, 4.8, and 6.0 mg/kg. The primary objective was to evaluate the safety and tolerability of BAT8001. Preliminary activity of BAT8001 was also assessed as a secondary objective.ResultsBetween March 2017 to May 2018, 29 HER2-positive breast cancer patients were enrolled. The observed dose-limiting toxicities were grade 4 thrombocytopenia and grade 3 elevated transaminase. The maximum tolerated dose was determined to be 3.6 mg/kg. Grade 3 or greater adverse events (AEs) occurred in 14 (48.3%) of 29 patients, including thrombocytopenia in 12 (41.4%) patients, aspartate aminotransferase increased in 4 (13.8%) patients, ?-glutamyl transferase increased in 2 (6.9%) patients, alanine aminotransferase increased in 2 (6.9%) patients, diarrhea in 2 (6.9%) patients. Objective response was observed in 12 (41.4%; 95% confidence interval [CI] = 23.5%-61.1%) and disease control (including patients achieving objective response and stable disease) was observed in 24 (82.8%; 95% CI = 64.2%-94.2%) patients.ConclusionsBAT8001 demonstrated favorable safety profiles, with promising anti-tumor activity in patients with HER2-positive locally advanced or metastatic breast cancer. BAT8001 has the potential to provide a new therapeutic option in patients with metastatic HER2-positive breast cancer.

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Dataset Information

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

Publications

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

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