Davalintide

Pramlintide is an equipotent amylin analogue that reduces food intake and body weight in obese subjects and has been clinically approved as an adjunctive therapy for the treatment of adult diabetic patients. However, due to its extremely short half-life in vivo, a regimen of multiple daily administrations is required for achieving clinical effectiveness. Herein is described the development of prototypical long-acting pramlintide bioconjugates, in which pramlintide's disulfide-linked macrocycle was replaced by a cyclic thioether motif. This modification enabled stable chemical conjugation to a half-life extending antibody. In contrast to pramlintide (t_1/2 < 0.75 h), bioconjugates 35 and 38 have terminal half-lives of ∼2 days in mice and attain significant exposure levels that are maintained up to 7 days. Single dose subcutaneous administration of 35 in lean mice, given 18-20 h prior to oral acetaminophen (AAP) administration, significantly reduced gastric emptying (as determined by plasma AAP levels). In a separate study, similar administration of 35 in fasted lean mice effected a reduction in food intake for up to 48 h. These data are consistent with durable amylinomimetic responses and provide the basis for further development of such long-acting amylinomimetic conjugates for the potential treatment of obesity and associated pathologies.

Since the discovery of insulin, a century ago, the repertoire of therapeutic polypeptides targeting diabetes - and now also obesity - have increased substantially. The focus on quality has shifted from impure and unstable preparations of animal insulin to highly pure, homologous recombinant insulin, along with other peptide-based hormones and analogs such as amylin analogs (pramlintide, davalintide, cagrilintide), glucagon and glucagon-like peptide-1 receptor agonists (GLP-1, liraglutide, exenatide, semaglutide). Proper formulation, storage, manipulation and usage by professionals and patients are required in order to avoid agglomeration into high molecular weight products (HMWP), either amorphous or amyloid, which could result in potential loss of biological activity and short- or long-term immune reaction and silent inactivation. In this narrative review, we present perspective of the aggregation of therapeutic polypeptides used in diabetes and other metabolic diseases, covering the nature and mechanisms, analytical techniques, physical and chemical stability, strategies aimed to hamper the formation of HMWP, and perspectives on future biopharmaceutical developments.