Evaluation of Safety and Efficacy of a Single Lorecivivint Injection in Patients with Knee Osteoarthritis: A Multicenter, Observational Extension Trial.

Introduction: Lorecivivint (LOR), a CDC-like kinase/dual-specificity tyrosine kinase (CLK/DYRK) inhibitor thought to modulate inflammatory and Wnt pathways, is being developed as a potential intra-articular knee osteoarthritis (OA) treatment. The objective of this trial was to evaluate long-term safety of LOR within an observational extension of two phase 2 trials.

Methods: This 60-month, observational extension study (NCT02951026) of a 12-month phase 2a trial (NCT02536833) and 6-month phase 2b trial (NCT03122860) was administratively closed after 36 months as data inferences became limited.

Individual Participant Symptom Responses to Intra-Articular Lorecivivint in Knee Osteoarthritis: Post Hoc Analysis of a Phase 2B Trial.

Introduction: Established thresholds for patient-reported outcomes (PROs) provide clinically relevant responder data from trials. Lorecivivint (LOR) is an intra-articular (IA) therapy in development for knee osteoarthritis (OA). A post hoc analysis from a phase 2b trial (NCT03122860) determined proportions of LOR responders.

Efficacy and tolerability of exenatide twice daily and exenatide once weekly in Asian versus White patients with type 2 diabetes mellitus: A pooled analysis.

Aims: The efficacy and safety of exenatide twice daily (BID) and once weekly (QW) were assessed in Asian versus White patients with type 2 diabetes mellitus (T2DM).

Methods: This post-hoc pooled analysis evaluated patients receiving 10μg exenatide BID for 12-30 weeks or 2mg exenatide QW for 24-30 weeks in exenatide clinical development program trials. Race was self-identified.

Diet-induced mouse model of fatty liver disease and nonalcoholic steatohepatitis reflecting clinical disease progression and methods of assessment.

Shortcomings of previously reported preclinical models of nonalcoholic steatohepatitis (NASH) include inadequate methods used to induce disease and assess liver pathology. We have developed a dietary model of NASH displaying features observed clinically and methods for objectively assessing disease progression. Mice fed a diet containing 40% fat (of which ∼18% was trans fat), 22% fructose, and 2% cholesterol developed three stages of nonalcoholic fatty liver disease (steatosis, steatohepatitis with fibrosis, and cirrhosis) as assessed by histological and biochemical methods.

Expenditures for medicaid patients treated with exenatide compared with other diabetes management regimens.

Objective: To compare Medicaid spending among patients with type 2 diabetes mellitus (T2DM) receiving exenatide or other add-on therapies.

Study Design: Medicaid data in patients with T2DM were compared among those who initiated exenatide, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, or basal insulin. Patients were on a regimen of metformin and/or sulfonylurea for 30 days and continued the next-line therapy for at least 90 days.

Emerging incretin based therapies for type 2 diabetes: incretin mimetics and DPP-4 inhibitors.

Type 2 diabetes is a chronic disease characterized by impaired insulin action, progressive beta cell dysfunction as well as abnormalities in pancreatic alpha cell function and postprandial substrate delivery. These pathophysiologic defects result in both persistent and progressive hyperglycemia, resulting in increased risk of both microvascular and cardiovascular complications. Traditional treatments for type 2 diabetes have focused on impaired insulin secretion and insulin resistance.

Pharmacokinetics and pharmacodynamics of exenatide following alternate routes of administration.

Exenatide is a 39-amino acid peptide incretin mimetic approved for adjunctive treatment of type 2 diabetes. It shares several glucoregulatory activities with the mammalian hormone, glucagon-like peptide-1 (GLP-1). In clinical use, subcutaneous exenatide injections demonstrate glucoregulatory and weight loss effects with sustained plasma concentrations in the 50-100 pM range.

Pharmacological actions of the peptide hormone amylin in the long-term regulation of food intake, food preference, and body weight.

The ability of amylin to reduce acute food intake in rodents is well established. Longer-term administration in rats (up to 24 days) shows a concomitant reduction in body weight, suggesting energy intake plays a significant role in mediating amylin-induced weight loss. The current set of experiments further explores the long-term effects of amylin (4-11 wk) on food preference, energy expenditure, and body weight and composition.

Effects of prior or concurrent food restriction on amylin-induced changes in body weight and body composition in high-fat-fed female rats.

Amylin infusion reduces food intake and slows body weight gain in rodents. In obese male rats, amylin (but not pair feeding) caused a preferential reduction of fat mass with protein preservation despite equal body weight loss in amylin-treated (fed ad libitum) and pair-fed rats. In the present study, the effect of prior or concurrent food restriction on the ability of amylin to cause weight loss was evaluated.

Efficient high-throughput discovery of large peptidic hormones and biomarkers.

A novel approach is presented for the simultaneous identification and relative quantification of secreted peptides, particularly those that have been historically difficult to analyze in a concerted manner. Peptides exceeding 60 residues with various degrees of post-translational modification were identified on a liquid chromatographic time scale. The approach demonstrates high efficiency pattern-based recognition analysis of complex neuroendocrine peptide sets and enables rapid identification of biomarkers from biological material.

Investigation of exenatide elimination and its in vivo and in vitro degradation.

Exenatide is a 39 amino acid incretin mimetic for the treatment of type 2 diabetes, with glucoregulatory activity similar to glucagon-like peptide-1 (GLP-1). Exenatide is a poor substrate for the major route of GLP-1 degradation by dipeptidyl peptidase-IV, and displays enhanced pharmacokinetics and in vivo potency in rats relative to GLP-1. The kidney appears to be the major route of exenatide elimination in the rat.

Immunogenicity of xenopeptide hormone therapies.

Peptides are a growing class of agents whose therapeutic use originated with non-human treatments such as animal insulins. Xenopeptides continue to be explored for biotherapeutic development using genetic engineering, and through the rich resource of animal and plant polypeptides. One of the major concerns of therapeutic administration of xenopeptides is the potential for untoward immune responses that may lead to loss of drug efficacy or adverse events in recipients.

Dose-response for glycaemic and metabolic changes 28 days after single injection of long-acting release exenatide in diabetic fatty Zucker rats.

Aims/hypothesis: Exenatide (exendin-4) injected subcutaneously twice daily reduces glycaemic deterioration in diabetic fatty Zucker (ZDF) rats and reduces HbA1c in humans with type 2 diabetes. Because tachyphylaxis may develop with continuous peptide exposure, we examined the activity of a long-acting-release (LAR) formulation of exenatide on HbA1c, insulin sensitivity and beta cell secretion in ZDF rats.

Methods: Single subcutaneous injections of a poly-lactide-glycolide microsphere suspension (3% peptide) containing 0, 1, 10, 100, 1,000, 3,000 or 9,000 mug exenatide were administered to 9-week-old ZDF rats with matched initial HbA1c values (n=7 rats/group).