ABSTRACT
This study aimed to evaluate the pharmacokinetics (PKs), safety, and immunogenicity of the biosimilar HEC14028 compared to reference Trulicity® (dulaglutide) in healthy male Chinese subjects. This study was a single-center, randomized, open, single-dose, parallel-controlled comparative Phase I clinical trial, including a screening period of up to 14 days, a 17-day observation period after administration, and a 7-day safety follow-up period. A total of 68 healthy male subjects were randomly assigned (1:1) to the test group (HEC14028) and the reference group (dulaglutide) (single 0.75 mg abdominal subcutaneous dose). The primary objective was to evaluate the pharmacokinetic characteristics of HEC14028 and compare the pharmacokinetic similarities between HEC14028 and dulaglutide. The primary PK endpoints were maximum plasma concentration (Cmax) and area under the blood concentration-time curve from zero time to the estimated infinite time (AUC0-∞). The study results showed that HEC14028 and dulaglutide were pharmacokinetically equivalent: 90% confidence interval (CI) of Cmax and AUC0-∞ geometric mean ratios were 102.9%-122.0% and 97.1%-116.9%, respectively, which were both within the range of 80.00%-125.00%. No grade 3 or above treatment emergent adverse events (TEAEs), serious adverse events (SAEs), TEAEs leading to withdrawal from the trial, or TEAEs leading to death were reported in this study. Both HEC14028 and dulaglutide showed good and similar safety profiles, and no incremental immunogenicity was observed in subjects receiving HEC14028 and dulaglutide.
Subject(s)
Biosimilar Pharmaceuticals , Glucagon-Like Peptides , Glucagon-Like Peptides/analogs & derivatives , Healthy Volunteers , Immunoglobulin Fc Fragments , Recombinant Fusion Proteins , Humans , Male , Immunoglobulin Fc Fragments/administration & dosage , Immunoglobulin Fc Fragments/adverse effects , Immunoglobulin Fc Fragments/immunology , Glucagon-Like Peptides/pharmacokinetics , Glucagon-Like Peptides/administration & dosage , Glucagon-Like Peptides/adverse effects , Recombinant Fusion Proteins/pharmacokinetics , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/adverse effects , Biosimilar Pharmaceuticals/pharmacokinetics , Biosimilar Pharmaceuticals/administration & dosage , Biosimilar Pharmaceuticals/adverse effects , Adult , Young Adult , China , Area Under Curve , Asian People , Therapeutic Equivalency , Injections, Subcutaneous , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/adverse effects , Middle Aged , Adolescent , East Asian PeopleABSTRACT
This study aimed to evaluate the pharmacokinetics (PKs), safety, and immunogenicity of the biosimilar (RD12014) compared to reference liraglutide (Victoza) in healthy Chinese male subjects, so as to provide the basis for the similarity evaluation of the two drugs. Eligible subjects were randomized 1:1 to two sequences (RD12014-Victoza or Victoza-RD12014). Subjects received a single 0.6 mg dose of Victoza or RD12014 by abdominal subcutaneous injection during the first period. After a 7-day washout period, subjects received the alternative drug during the second period. Blood samples were collected at predefined timepoints for PKs and immunogenicity assessment. The primary PK end points were maximum plasma concentration (Cmax ) and area under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUC0-last ). PK bioequivalence was achieved, if the 90% confidence intervals (CIs) of the geometric mean ratio (GMR) of Cmax and AUC0-last were within the range of 80.00-125.00%. Safety was assessed throughout the study. The 90% CIs of the GMR of RD12014 to Victoza for Cmax and AUC0-last were completely within the range of 80.00-125.00%. Thirteen treatment-related adverse events (TRAEs) were reported in 11 subjects (22.4%) in the RD12014 group, compared to 12 TRAEs reported in 12 subjects (24.5%) in the Victoza group. The blood samples of 49 subjects were negative for anti-drug antibody and the neutralizing antibody was not further detected. This study demonstrated PK similarity of RD12014 to Victoza in healthy Chinese male subjects. Safety and immunogenicity profiles were comparable between the two groups.
Subject(s)
Biosimilar Pharmaceuticals , Liraglutide , Humans , Male , Biosimilar Pharmaceuticals/adverse effects , Biosimilar Pharmaceuticals/pharmacokinetics , China , Healthy Volunteers , Liraglutide/adverse effects , Liraglutide/pharmacokinetics , Therapeutic EquivalencyABSTRACT
BACKGROUND: Fibroblast growth factor 21 (FGF21) has become a promising therapeutic target for metabolic diseases such as type 2 diabetes (T2D), obesity and non-alcoholic steatohepatitis. However, the clinical application of natural FGF21 molecule is limited because of its instability in vitro and short half-life in vivo. To improve FGF21's therapeutic property, we screened high receptor binding FGF21 analogs and made FGF21-Fc-GLP-1 dual-targeted constructs to investigate their activity in a number of experiments . METHODS: Utilizing phage display high-throughput screening we identified mutations that could improve ß-Klotho binding property of FGF21. IgG4 Fc was fused to FGF21 variants to extend the in vivo half-life. We further explored the potential synergistic actions of FGF21 with the incretin glucagon-like peptide-1 (GLP-1) by generating GLP-1-Fc-FGF21 dual agonists. FINDINGS: Two Fc-FGF21 variants showed enhanced ß-Klotho binding affinity in vitro as well as improved glucose lowering effect in vivo. One of the dual agonists, GLP-1-Fc-FGF21 D1, provided potent and sustained glucose lowering effect in diabetic mice models. It also demonstrated superior weight loss effect to GLP-1 or FGF21 alone. Moreover, GLP-1-Fc-FGF21 D1 exhibited strong anti-NASH effect in the high-fat diet-induced ob/ob model as it improved liver function, serum and hepatic lipid profile and reduced NAFLD activity score with an efficacy superior to either FGF21 or GLP-1 analogs alone. INTERPRETATION: This novel GLP-1/FGF21 dual agonist is worth clinical development for the treatment of T2D, obesity and NASH. FUNDING: HEC Pharm R&D Co., Ltd, National natural science fund of China.
Subject(s)
Fibroblast Growth Factors/agonists , Glucagon-Like Peptide 1/agonists , Hypoglycemic Agents/pharmacology , Recombinant Fusion Proteins/pharmacology , Animals , Blood Glucose/drug effects , Body Weight/drug effects , Cell Line , Diabetes Mellitus, Experimental/drug therapy , Diet, High-Fat , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Discovery , Fibroblast Growth Factors/genetics , Fibroblast Growth Factors/metabolism , Glucagon-Like Peptide 1/genetics , Glucagon-Like Peptide 1/metabolism , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/pharmacokinetics , Mice , Non-alcoholic Fatty Liver Disease/drug therapy , Rats , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/pharmacokinetics , Treatment OutcomeABSTRACT
Cyanovirin-N (CVN) is a promising antiviral candidate that has an extremely low sequence homology with any other known proteins. The efficient and soluble expression of biologically functional recombinant CVN (rCVN) is still an obstacle due to insufficient yield, aggregation, and abnormal modification. Here, we describe an improved approach to preparing native rCVN from Escherichia coli more efficiently. A fusion gene consisting of cvn and sumo (small ubiquitin-related modifier) and a hexahistidine tag was constructed according to the codon bias of the host cell. This small ubiquitin-related modifier (SUMO)-fused CVN is expressed in the cytoplasm of E. coli in a folded and soluble form (>30% of the total soluble protein), yielding 3 to 4 mg of native rCVN from 1 g of wet cells to a purity up to 97.6%. Matrix-assisted laser desorption ionization coupled to time-of-flight mass spectrometry and reverse-phase high-performance liquid chromatographic analysis showed that the purified rCVN was an intact and homogeneous protein with a molecular weight of 11,016.68 Da. Potent antiviral activity of rCVN against herpes simplex virus type 1 and human immunodeficiency virus type 1/IIIB was confirmed in a dose-dependent manner at nanomolar concentrations. Thus, the His-SUMO double-fused CVN provides an efficient approach for the soluble expression of rCVN in the cytoplasm of E. coli, allowing an alternative system to develop bioprocess for the large-scale production of this antiviral candidate.
