The rising obesity rate across all age groups underlines the dramatic increase in the incidence of diabetesin the United States. According to CDC, 34.2 million people or 10.5% of U.S. population have diabetes in 2018,with an estimated total cost of $327 billion to the healthcare system. The medical community has recognizedthat diabetes treatments should ideally lead to both blood glucose control and bodyweight loss. The mission ofTransira Therapeutics is to develop an innovative best-in-class oral peptide drug for the treatment of thediabetes and obesity using our proprietary peptide stapling chemistry. The goal of this project is to develop achemically modified peptide dual agonist of GIPR/GLP-1R as a once-daily oral drug for the treatment ofdiabetes and obesity. In our preliminary studies, we identified two stapled peptides that show biased dual GIPand GLP-1 receptor agonists along with the drastically improved proteolytic stability and robust in vivo glucose-lowering efficacy. In this SBIR phase I application, we have two specific aims: (1) Synthesis and evaluation ofthe chimeric GIPR/GLP-1R peptide dual agonists containing a lipid-modified chemical stapler for improved oralbioavailability; and (2) Preclinical assessment of the pharmacokinetics, glucose control, bodyweight reduction,and other metabolic effects of the orally administered GIPR/GLP-1R peptide dual agonist in DIO mice. Weexpect to identify one fatty diacid-containing biaryl-stapled peptide that exhibits Papp value >100 times greaterthan semaglutide (with a permeation enhancer if necessary) in the Caco-2 cell monolayer transport assay andglucose-lowering efficacy greater than or equal to semaglutide in oral glucose tolerance test (OGTT). Also, weexpect the lipid-containing stapled peptide to show greater oral bioavailability than oral semaglutide, >25%decrease in fasting glucose levels in intraperitoneal glucose tolerance test (IPGTT), and >20% bodyweightreduction after PO administration compared to placebo in DIO mice. The successful completion of the phase Istudies should lay a solid foundation for the IND-enabling phase II studies in the future.
Public Health Relevance Statement: Narrative
In combating the rising incidence of diabetes to the epidemic proportion in the U.S., diabetes treatments should
ideally lead to both blood glucose control and bodyweight reduction. This project aims to develop an innovative
best-in-class oral peptide drug for the treatment of diabetes and obesity through the synthesis and preclinical
evaluation of our proprietary, chemically modified peptide dual agonist in DIO mice.
Project Terms: absorption ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Biological Availability ; Bioavailability ; Biologic Availability ; Physiologic Availability ; Blood Glucose ; Blood Sugar ; Centers for Disease Control and Prevention (U.S.) ; CDC ; Centers for Disease Control ; Centers for Disease Control and Prevention ; United States Centers for Disease Control ; United States Centers for Disease Control and Prevention ; Chemistry ; Communities ; Diabetes Mellitus ; diabetes ; Non-Insulin-Dependent Diabetes Mellitus ; Adult-Onset Diabetes Mellitus ; Ketosis-Resistant Diabetes Mellitus ; Maturity-Onset Diabetes Mellitus ; NIDDM ; Non-Insulin Dependent Diabetes ; Noninsulin Dependent Diabetes ; Noninsulin Dependent Diabetes Mellitus ; Slow-Onset Diabetes Mellitus ; Stable Diabetes Mellitus ; T2 DM ; T2D ; T2DM ; Type 2 Diabetes Mellitus ; Type 2 diabetes ; Type II Diabetes Mellitus ; Type II diabetes ; adult onset diabetes ; ketosis resistant diabetes ; maturity onset diabetes ; type 2 DM ; type II DM ; type two diabetes ; Diagnosis ; Pharmacotherapy ; Drug Therapy ; drug treatment ; Epidemic ; Exhibits ; Nonesterified Fatty Acids ; Free Fatty Acids ; Foundations ; Future ; Glucose ; D-Glucose ; Dextrose ; Glucose tolerance test ; IPGTT ; intraperitoneal glucose tolerance test ; Goals ; Hand ; Healthcare Systems ; Health Care Systems ; In Vitro ; Incidence ; Insulin ; Humulin R ; Novolin R ; Regular Insulin ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Lipids ; Metabolic Diseases ; Metabolic Disorder ; Thesaurismosis ; metabolism disorder ; Obese Mice ; ob/ob mouse ; Mission ; Mus ; Mice ; Mice Mammals ; Murine ; New York ; Obesity ; adiposity ; corpulence ; OGTT ; Oral Glucose Tolerance Test ; Legal patent ; Patents ; Peptides ; Permeability ; Drug Kinetics ; Pharmacokinetics ; Placebos ; Sham Treatment ; sham therapy ; Plasma ; Blood Plasma ; Plasma Serum ; Reticuloendothelial System, Serum, Plasma ; Prodrugs ; Drug Precursors ; Pro-Drugs ; Publishing ; Research ; Sodium ; Na element ; statistics ; Tablets ; Technology ; Time ; Triglycerides ; Triacylglycerol ; United States ; Universities ; Enhancers ; dosage ; improved ; Chronic ; Solid ; Phase ; Medical ; Chemicals ; Evaluation ; Serum ; Blood Serum ; Agonist ; Caco-2 Cells ; CaCo2 ; Therapeutic ; Metabolic ; programs ; ACRP30 protein ; adipocyte complement-related protein 30-kDa ; adipocyte, C1q and collagen domain containing protein ; apM-1 protein ; apM1 (adipose-specific) protein ; adiponectin ; Oral ; age group ; chemical stability ; Peptide Hormone Gene ; peptide hormone ; Receptor Protein ; receptor ; success ; Agreement ; Reporting ; Position ; Positioning Attribute ; monolayer ; Manufacturer ; Manufacturer Name ; GIPR ; GIPR gene ; Research Contracts ; in vivo ; Small Business Innovation Research Grant ; SBIR ; Small Business Innovation Research ; Development ; developmental ; pre-clinical ; preclinical ; preclinical study ; pre-clinical study ; cost ; design ; designing ; blood glucose regulation ; glucose control ; glucose homeostasis ; glucose regulation ; Population ; innovation ; innovate ; innovative ; driving force ; mouse model ; murine model ; Biological Markers ; bio-markers ; biologic marker ; biomarker ; preclinical evaluation ; pre-clinical evaluation ; good laboratory practice ; fasting glucose ; comparative efficacy ; compare efficacy ; drug candidate ; phase 1 study ; Phase I Study ; phase 2 study ; phase II study ; peptide drug ; therapeutic peptide ; efficacy study ; diet-induced obesity ; diet-associated obesity ; diet-related obesity ; pre-clinical assessment ; preclinical assessment ;
