Co-Formulations of Amylin Analogues with Insulin Analogues for Treatment of Diabetes

PROJECT SUMMARY
The ultimate goal of the proposed work is to develop a novel co-formulation of insulin analogues (e.g. lispro
and aspart) with an amylin analogue (e.g. pramlintide) and with incretin hormones (e.g. liraglutide), to enable a
transformational new treatment for diabetes constituting a true replacement therapy. The most challenging
aspect of optimal glycemic control for the 1.45 million people with type 1 diabetes (T1D) in the United States is
limiting large increases in blood glucose after a meal. People with type 1 diabetes do not produce the insulin
required for the body to process glucose, so insulin must be replaced by daily injections. Amylin is a small
peptide hormone excreted alongside insulin by pancreatic β islet cells that acts centrally to slow gastric
emptying, suppress postprandial glucagon secretion, and decrease food intake, thus complementing the action
of insulin to regulate blood glucose levels. Similar to insulin, amylin production is completely absent in
individuals with type 1 diabetes on account of their lack of pancreatic β cells. T1D is also characterized by
abnormal suppression of glucagon secretion in response to hyperglycemia. Glucagon-like peptide-1 (GLP-1) is
an incretin hormone and neurotransmitter secreted from intestinal L-cells in response to nutrients to stimulate
insulin and suppress glucagon secretion in a glucose-dependent manner. Long-acting GLP-1 receptor agonists
(GLP-1 RAs) have become central to the treatment of diabetes and while these drugs are not yet approved for
T1D patients, GLP-1 RAs appear to be well tolerated in patients with T1D and could have beneficial effects in
both new onset and longstanding T1D patients. As an adjunctive therapy to insulin, GLP-1 RAs can improve
glycemic control and body weight in longstanding disease while also reducing insulin requirements in T1D
patients. Current administration regimens for these therapeutics are highly burdensome as they must be
injected either daily or weekly or taken daily orally. A true replacement therapy, therefore, would administer
both amylin and insulin simultaneously, while also delivering GLP-1 RAs. Unfortunately, Symlin (Pramlintide;
AstraZeneca), the only commercial amylin analogue formulation, is formulated at pH~4 while Novolog (Aspart;
Novonordisk) and Humalog (Lispro; Eli Lilly), insulin analogue formulations, are typically formulated at pH~7.4,
meaning that these formulations are incompatible and must be administered in separate injections. While
treatment of diabetes with separate injections of insulin and amylin analogues at mealtimes has been shown to
be much more effective than insulin alone at managing diabetes, the administration of two separate injections
is burdensome. We have developed a novel polymeric excipient that results in stable, ultra-fast acting insulin,
to formulate insulin and pramlintide together to enable a single administration treatment mimicking endogenous
hormone secretion. Additionally, we can effectively incorporate GLP-1 RAs into these formulations. This novel
combination therapy will yield unprecedented postprandial glycemic control and catalyze the development of a
powerful tool for the management of diabetes affording thus far unrealized therapeutic impact.

Grant Number: 2R56DK119254-06
NIH Institute/Center: NIH
Principal Investigator: Eric Appel