Objective
We will develop an ultra-fast insulin-amylin co-formulation drug product capable of enhancing mealtime glycemic control and improving diabetes management. We will leveraging a novel copolymer excipient technology developed in our lab, which demonstrates unprecedented ability to stabilize proteins in formulation, to co-formulate monomeric insulin and pramlintide together in co-formulation. We hypothesize that combining monomeric insulin and pramlintide will result in an ultra-fast insulin pharmacokinetic profile with essentially perfect overlap between the two proteins to better mimic endogenous co-secretion of the two hormones. We have promising proof-of-concept data suggesting that stable co-formulation of these two hormones with our novel excipient technology is possible, and that these two proteins exhibit ultrafast pharmacokinetics and almost perfect overlap in exposure in a rat model of type 1 diabetes. We have assembled a team with relevant expertise to successfully achieve our research goals, and propose the following aims to develop an insulin-pramlintide co-formulation drug product providing thus far unrealized therapeutic benefit:
Aim 1: Develop and characterize the formulation stability of insulin-pramlintide co-formulations.
Aim 1a: Optimize insulin-pramlintide co-formulations.
Aim 1b: Comprehensively characterize co-formulation stability.
Aim 2: Optimize insulin-pramlintide co-formulation ratios in diabetic pigs.
Aim 2a: Evaluate pharmacokinetics of insulin-pramlintide co-formulations.
Aim 2b: Evaluate the impact of insulin-pramlintide formulations on gastric-emptying.
Aim 3: Evaluate 28-day safety and tolerability following repeated-dosing of co-formulations in rats
Aim 3a: Evaluate blood chemistry at week two and at the endpoint of the study.
Aim 3b: Evaluate histopathology of liver, kidney, heart, brain and injection site at study endpoint.
Background Rationale
Studies have shown that dual-hormone replacement therapy with insulin and amylin analogues results in improved glycemic outcomes for individuals with diabetes over treatment with insulin alone. The burdensome requirement of separate injections of insulin and pramlintide at mealtimes has severely limited the clinical use of dual-hormone therapy. While current clinical studies with insulin-pramlintide co-formulation products (e.g., M1Pram from Adocia) comprising a fixed insulin-pramlintide ratio have demonstrated some early clinical success, the co-formulation was found to be generally similar to the standard approach of separate administration of insulin and pramlintide as this formulation did not improve the disparate exposure timeframes of the insulin and pramlintide species in the co-formulation.
Recent work from our group exploited an approach to non-covalent PEGylation with a designer excipient CB[7]-PEG to create an insulin-pramlintide co-formulation exhibiting increased overlap in insulin and pramlintide exposure in diabetic pigs. This non-covalent PEGylation approach worked by extending pramlintide exposure to match insulin exposure more closely. These more similar pharmacokinetics resulted in improved glucagon suppression in diabetic pigs than when the two hormones were dosed separately in standard commercial formulations. Unfortunately, this benefit came at the expense of slower pharmacokinetics. An ideal meal-time insulin-pramlintide co-formulation would have ultrafast kinetics of both insulin and pramlintide and improved exposure overlap that would more closely mimic endogenous co-secretion of the two hormones.
In this work we will develop an ultra-fast co-formulation drug product comprising monomeric insulin and pramlintide by leveraging a novel copolymer excipient invented in our lab at Stanford University. This copolymer excipient has demonstrated unprecedented ability to stabilize proteins in formulation by blocking their ability to aggregate at interfaces. The propensity of insulin and pramlintide to aggregate to form amyloid fibrils, which are primarily initiated at interfaces, makes them strong candidates for stabilization using our novel excipient technology. We have already generated promising proof-of-concept data in diabetic rats with a prototype ultrafast co-formulation of monomeric insulin lispro and pramlintide that exhibits greater overlap of exposure and improved glycemic control after a glucose challenge. We propose to comprehensively evaluate the synergistic effects arising from the improved pharmacokinetics and exposure overlap of these two hormones on gastric emptying, post-prandial glycemic control, and post-prandial glucagon suppression in diabetic pigs to support optimization of the co-formulation prior to clinical translation. We believe this novel dual-hormone therapy has the potential to yield unprecedented postprandial glycemic control and catalyze the development of a powerful tool for the management of diabetes affording thus far unrealized therapeutic impact.
Description of Project
The most challenging aspect of optimal glycemic control for the 1.25 million people with type 1 diabetes (T1D) in the United States is limiting large increases in blood glucose after a meal. T1D is characterized by the inability to produce endogenous insulin and amylin after an autoimmune response destroys the pancreatic beta-cells. In individuals without diabetes, insulin and amylin work synergistically to control post-prandial glucose. Insulin promotes cellular glucose uptake, while amylin delays gastric emptying, increases satiety, and suppresses glucagon action. Treatment of T1D over the last 100 years has primarily focused on insulin replacement; however, studies have shown that dual-hormone replacement therapy with insulin and amylin analogues results in improved glycemic outcomes for individuals with diabetes over treatment with insulin alone. While a commercially available amylin analogue called pramlintide exists, it cannot be co-formulated with insulin using traditional formulation approaches. Indeed, Symlin (pramlintide; AstraZeneca) is formulated at pH~4 while Novolog (insulin aspart; Novo Nordisk) and Humalog (insulin lispro; Eli Lilly) are typically formulated at pH~7.4. The burdensome requirement of separate injections of insulin and pramlintide at mealtimes has severely limited the use of dual-hormone therapy. Additionally, the distinct pharmacokinetics of traditional rapid-acting insulin formulations (e.g, Humalog and Novolog) and the pramlintide formulation (Symlin), coupled with poor control of dosing of the two separate drugs, fails to recapitulate endogenous co-secretion of these hormones. While current clinical studies with insulin-pramlintide co-formulation products (e.g., M1Pram from Adocia) comprising a fixed insulin-pramlintide ratio have demonstrated some clinical success, the co-formulation was found to be generally similar to the standard approach of separate administration of insulin and pramlintide on account of the distinct pharmacokinetics of the insulin and pramlintide species in the co-formulation.
In this work we will develop an ultrafast insulin-pramlintide co-formulation drug product candidate that exhibits near perfect overlap in insulin and pramlintide exposure to more closely mimic endogenous co-secretion of these two hormones to improve their synergistic action. We have promising proof-of-concept pharmacokinetic and efficacy data in a rat model of insulin-deficient diabetes that demonstrates the feasibility of this approach and enhanced synergy in insulin and pramlintide action. We have assembled a team with relevant expertise to successfully achieve our research goals and believe this novel dual-hormone therapy will dramatically improve postprandial glycemic control and afford thus far unrealized therapeutic impact in diabetes management.
Anticipated Outcome
Currently available dual-hormone treatments with insulin and amylin require burdensome separate injections at mealtimes and have disparate pharmacokinetics that do not mimic endogenous co-secretion of these two hormones. By leveraging our novel copolymer excipient technology, we will create a co-formulation of monomeric insulin lispro and pramlintide that exhibits synchronous and ultrafast pharmacokinetics, as well as greater stability than commercial fast-acting insulin formulations such as Humalog. We already have promising proof-of-concept data in vitro and in diabetic rats demonstrating that this is possible. We hypothesize that this novel co-formulation will exhibit greater synergy between the two hormones that could allow for improved glucagon suppression and slowed gastric emptying at lower pramlintide doses than seen with previous co-formulation drug product candidates.
Beyond improved mealtime glycemic control through subcutaneous administration of our new co-formulation, delivering an insulin-pramlintide formulation with these synchronous ultrafast pharmacokinetics presents opportunities for applications in infusion pumps and “artificial pancreas” closed-loop systems. Studies using two separate pumps delivering insulin and pramlintide at a fixed ratio has been used in a closed-loop system and shown increased time-in-range compared to treatment with insulin alone. A stable and ultrafast insulin-pramlintide co-formulation would enable better autonomous hormone replacement therapy in closed-loop systems outside of clinical trials where using two separate infusion pumps is impractical. At present, these closed-loop systems require patients to input carbohydrates counts at mealtimes and are not fully autonomous, in part because insulin absorption kinetics are not rapid enough to reduce mealtime glucose excursions, and the extended duration of insulin action can result in “insulin stacking” leading to post-prandial hypoglycemia. An ultrafast insulin-pramlintide co-formulation has the potential to rapidly react to mealtime spikes and reduce the risk of hypoglycemia resulting from insulin stacking.
We anticipate that the ultrafast dual-hormone drug product we propose to develop and evaluate in these studies will result in improved glucose management and reduced patient burden in clinical applications using it for both direct bolus administration as well as in insulin infusion pumps or artificial pancreas closed-loop systems. The proposed work has the potential to catalyze the development of a powerful tool for the management of diabetes affording thus far unrealized therapeutic impact.
Relevance to T1D
The most challenging aspect of optimal glycemic control for the 1.25 million people with type 1 diabetes (T1D) in the United States is limiting large increases in blood glucose after a meal. T1D is characterized by the inability to produce endogenous insulin and amylin after an autoimmune response destroys the pancreatic beta-cells. In individuals without diabetes, insulin and amylin work synergistically to control post-prandial glucose. Insulin promotes cellular glucose uptake, while amylin delays gastric emptying, increases satiety, and suppresses glucagon action. Treatment of T1D over the last 100 years has primarily focused on insulin replacement; however, studies have shown that dual-hormone replacement therapy with insulin and amylin results in improved glycemic outcomes for individuals with diabetes over treatment with insulin alone. While a commercially available amylin analogue called pramlintide exists, it cannot be co-formulated with insulin using traditional formulation approaches. Indeed, Symlin (pramlintide; AstraZeneca) is formulated at pH~4 while Novolog (insulin aspart; Novo Nordisk) and Humalog (insulin lispro; Eli Lilly) are typically formulated at pH~7.4. The burdensome requirement of separate injections of insulin and pramlintide at mealtimes has severely limited the use of dual-hormone therapy. Additionally, the distinct pharmacokinetics of traditional rapid-acting insulin formulations (e.g, Humalog and Novolog) and the pramlintide formulation (Symlin), coupled with poor control of dosing of the two separate drugs, fails to recapitulate endogenous co-secretion of these hormones. While current clinical studies with insulin-pramlintide co-formulation products (M1Pram; Adocia) comprising a fixed insulin-pramlintide ratio have demonstrated some success, the co-formulation was found to be generally similar to the standard approach of separate administration of insulin and pramlintide on account of the distinct pharmacokinetics of the insulin and pramlintide species in the co-formulation.
In this work we will develop an ultrafast insulin-pramlintide co-formulation drug product candidate that exhibits near perfect overlap in insulin and pramlintide exposure to more closely mimic endogenous co-secretion of these two hormones to improve their synergistic action. We believe this novel dual-hormone therapy will dramatically improve postprandial glycemic control and afford thus far unrealized therapeutic impact in diabetes management.