The Solution is Dual Hormone
Automated Insulin Delivery

How should pramlintide dosing be altered to improve efficacy and tolerability?  We’ve considered the following strategies:

  • Dual hormone automated insulin delivery (AID) systems

  • Other formulations and devices

The remainder of Part 2 will discuss each of these approaches.

Dual hormone AID systems

Our view is that the way to administer both insulin and amylin in a fashion that most closely mimics normal human physiology is to use AID technology.  Back in the 1990s, when development of pramlintide was started, the idea of pumping pramlintide never came up, because it would have been commercially impossible.  Today the idea of a dual hormone AID system is not only a practical consideration, it is actively under development at Beta Bionics (Boston) and Inreda Diabetic (Netherlands), as illustrated in Exhibit 16. [1] [2]

 
Exhibit 16.JPG
 

Both pumps have been designed to infuse insulin and glucagon; the idea is that iatrogenic hypoglycemia can be mitigated by infusing glucagon to arrest declining blood glucose.  The main challenge has been the availability of a stable glucagon formulation that could be stored in the pump cartridges.  Not only has pramlintide been shown to be stable at room temperature while in use by patients, but pump studies have already demonstrated the feasibility of pumping pramlintide.

So, these dual chamber pumps could be repurposed to infuse pramlintide.  Two alternative amylin infusion algorithms are plausible:

  • Independent amylin algorithm: Pramlintide infusions would be determined by a separate dosing algorithm.  A new amylin algorithm would be designed to reflect the differing magnitudes of basal and bolus levels required to correctly manage blood glucose influx. 

  • Insulin-dependent amylin algorithm: Pramlintide infusions would be determined as a ratio to insulin infusions, with the basal and bolus infusion ratios being different to reflect the differences in diurnal hormone profiles. 

Our view is that the second, “Dual Ratio Amylin/Insulin” (DRAI) algorithm is likely to be the best approach to delivering an amylin analog via an AID system, as we now explain.

All AID systems incorporate dosing algorithms which deliver two types of infusions:

  • Basal:  A continuous, slow rate of insulin infusion interrupted only when blood glucose is projected to drop into hypoglycemia territory.  During this period the ratio of circulating amylin/insulin should be highest to maintain the tonic inhibition of alpha-cells.

  • Bolus:  Short bursts of insulin infusion used at mealtimes to counteract the influx of glucose from the gut.  During these periods the ratio of circulating amylin/insulin should be lower to avoid triggering nausea while suppressing glucagon and slowing gastric emptying.

Decreasing the amylin/insulin ratio during bolus infusions would prevent the nausea-inducing spikes at mealtimes; increasing the basal infusion rate would maintain the tonic inhibition of alpha-cells between meals.  The ability to dial in different basal and bolus infusion ratios would be simple to implement, and the ratios could be tweaked to optimize the efficacy for individual patients.

Our calculations indicate that the following ratios would be a good starting point for clinical research (see Appendix B for derivation of these ratios):

 
A-I Ratios.JPG
 

In silico modelling predicted an optimal ratio of 9 µg/U, and a recently completed dual hormone AID study used a ratio of 6 µg/U, and these ratios are consistent with our dual ratio calculations. [3] [4]

Although there are not yet commercially available bihormonal pumps, clinical studies using separate pumps could begin immediately to validate the DRAI idea.  The earliest amylin pump study was reported in 2009 using separate pumps for pramlintide and insulin, so this approach has already been demonstrated as feasible. [5]

In addition to the DRAI system, the efficacy/tolerability problems with pramlintide dosing could probably be addressed in other ways, albeit with theoretically less efficacy:

  • Insulin/pramlintide blends

  • Long acting amylin agonists

  • Osmotic pumps


Insulin/pramlintide blends

Because the requirement for additional mealtime injections of pramlintide has been a significant barrier to patient acceptance, the idea of blending insulin with an amylin agonist for use with either multiple daily injections or in a pump has been a goal for a long time.

Several clinical studies have tested fixed ratios:

  • 2009 Heptulla et al:  24-hour basal-bolus infusions of 3, 4, or 5 µg/hour basal pramlintide was tested with bolus injections of 5 µg pramlintide per Unit of insulin.  Glucagon was suppressed postprandially but not between meals, and postprandial hyperglycemia was reduced 26%. [6]

  • 2018 Haidar et al: 24-hour fixed ratio basal-bolus infusions of 6 µg pramlintide per Unit insulin (regular and rapid).  With rapid acting insulin, time in range increased from 71% to 85%, and glucose variability decreased from 34% CV to 25% CV.  No improvement was shown with regular insulin. [7]

  • 2018 Riddle et al: 24-hour fixed ratio basal-bolus infusions of 9 µg pramlintide per Unit rapid insulin.  Postprandial increments in blood glucose were almost entirely suppressed when pramlintide was co-administered.  Time in range (70 to 180 mg/dl) increased from 50% to 62%, and postprandial glucagon AUCs decreased between 7% and 16%. [8]

Exhibit 17 presents the glucose results from the Riddle et al study.  Based on the AUCs in Exhibit 17, fixed ratio amylin infusions lowered the T1D estimated HbA1c from 8.0% to 7.3%.  However, this smoothed profile remained hyperglycemic compared to normal, healthy subjects having an estimated HbA1c of 4.7%. [9]

Exhibit 17.JPG

In the Riddle et al study, the total diurnal glucagon profile was smoothed but only lowered overall 4.3% based on AUCs (Exhibit 18).

Exhibit 18.JPG

Adverse events were increased, suggesting supraphysiological concentrations of pramlintide were reached at mealtimes:

 
Adverse Events.JPG
 

Two conclusions about this study seem reasonable:

  • A 24-hour period is probably too short for the dual hormone therapy to reach a more beneficial equilibrium, and it is certainly too short to test the amylin circuit-breaker theory by measuring a reduction in hypoglycemic events.

  • It’s likely that the dosing regimen tested was not optimal.  Bolus levels of pramlintide were probably too high, based on the adverse events, and basal levels may have been too low over night.

We believe a fixed ratio blend of insulin and amylin is not likely to achieve full efficacy in an AID system, especially the goal of restoring the glucagon counterregulatory response.

Two companies are known to be developing coformulations of insulin and pramlintide:

  • AstraZeneca:  In 2011 the JDRF and Amylin Pharmaceuticals (now merged into AstraZeneca) announced a collaboration to investigate coformulating pramlintide with insulin. [10] An October 2018 JDRF press release indicated that the Riddle et al study was a result of this collaboration, however, there is no visibility on AstraZeneca’s recent progress or plans.

  • Adocia:  This French company is developing a coformulation of pramlintide and rapid insulin. [11] In September 2018 Adocia reported results of a study comparing their coformulation to separate injections (Exhibit 19).  The results for slowing gastric emptying were equally equivalent comparing the coformulation to separate injections.  Assuming the Adocia coformulation is usable in pumps, testing of a fixed ratio insulin/amylin blend in an AID system should soon be feasible.

Exhibit 19.JPG

Formulations with pharmacokinetics of short-acting insulin and pramlintide could be used in:

  • Single channel AID systems: If the dosing ratio is designed to be optimal at mealtimes, clinical studies have demonstrated a dosing regimen that provides the amylin benefit of suppressing prandial glucagon secretion and slowing gastric emptying.  However, it is unlikely that tolerable prandial boluses of amylin would provide enough basal coverage between meals to activate tonic inhibition of alpha-cells secretion and recharge the counterregulation response.

  • Multiple daily injections:  Pramlintide dosing could be kept in the physiological range to provide amylin bolus benefits without overdose-induced nausea.  Data present above suggests 30 µg of pramlintide at mealtimes may be sufficient to suppress glucagon and slow gastric emptying, but insufficient to restore counterregulation without addition of a basal, long-acting amylin agonist.

We are pessimistic that short acting coformulations would be successful in restoring glucagon counterregulation without the addition of long-acting amylin agonists.


Long-acting amylin formulations

A long-acting amylin formulation might provide enough basal coverage to reactivate some or most of the glucagon counterregulatory mechanism.  A long-acting amylin agonist would be analogous to insulin glargine (LANTUS), i.e. with once daily injections.  Ideally the long-acting, basal amylin formulation could be used with a fixed-ratio, rapid-acting insulin/amylin blend at mealtimes.  In this way the ratios of basal vs. bolus amylin/insulin could be adjusted to optimize efficacy and tolerability.

Several companies have reported projects to develop long-acting amylin analogues for weight loss:

  • Novo-Nordisk reported that their long-acting amylin analog, AM833, was in Phase 2 as of February 2020, while a coformulation of AM833 and semaglutide (a GLP-1 agonist) was in Phase 1 testing. [12]

  • As of March 2020, Zealand Pharma’s website pipeline included a project to develop a long acting amylin agonist, BI-473494, which was projected to enter Phase 1  for an obesity indication during 2020. [13]

  • In April 2019 Biozeus Biopharmaceutical SA (Brazil) published preclinical data for their long-acting amylin analog, BZ043. [14] However, as of March 2020 this compound was not shown in clinical development on the company’s website.

Hopefully, at least one of these projects will lead to a commercially available, long-acting amylin analog that could be tested for restoring the glucagon counterregulatory response in T1D.


Implantable osmotic amylin pump

For delivery of basal hormone profiles, the concept of an implantable pump is conceptually attractive.  Intarcia (Boston) is working to commercialize an implantable osmotic pump that would deliver a GLP-1 agonist (exenatide) for six to twelve months.  Clinical results are encouraging, presumably in part because patient compliance issues are eliminated. [15]

Intarcia’s pump requires a high potency, body-temperature-stabilized formulation.  If such an amylin agonist formulation can be developed, it could be an alternative to long-acting amylin agonists.  However, in March 2020 the FDA rejected for the second time Intarcia’s application to market the GLP-1 pump, so development of an amylin pump is unlikely any time soon.

* * * * * * *

In summary:

  • Beta-cells produce two hormones probably because influx and efflux diurnal profiles need to be different.

  • The difference between insulin and amylin diurnal profiles is caused by differences in clearance and secretion rates.

  • The amylin diurnal profile emphasizes basal exposure, compared to the more bolus-oriented insulin profile.

  • Mealtime injections of pramlintide result in prandial overdosing and postabsorptive underdosing, which results in poor tolerability and efficacy.

  • A bihormonal AID system using different amylin/insulin ratios for basal and bolus infusions would be the optimal way to correctly mimic both insulin and amylin diurnal plasma profiles.

These observations are readily tested with available technology.  In Part 3 we begin the process of designing the research programs needed to validate the amylin circuit-breaker hypothesis.

Endnotes:

[1]  Home use of a bihormonal bionic pancreas versus insulin pump therapy in adults with type 1 diabetes: a multicenter randomized crossover trial; Lancet 389:369-80 2017.

[2]  Performance and safety of an integrated bihormonal artificial pancreas for fully automated glucose control at home; Diabetes, Obesity and Metabolism 18:671-7 2016.

[3]  In silico design of optimal ratio for co-administration of pramlintide and insulin in type 1 diabetes; Diabetes Technology & Therapeutics 15:802-9 2013.

[4]  A Novel Dual-Hormone Insulin and Pramlintide Artificial Pancreas for Type 1 Diabetes: A Randomized Controlled Crossover Trial; 43:597-606 2020.

[5]  Twenty-four-hour simultaneous subcutaneous basal-bolus administration of insulin and amylin in adolescents with type 1 diabetes decreases postprandial hyperglycemia; J Clin Endocrinol Metab 94:1608-11 2009.

[6]  Twenty-Four-Hour Simultaneous Subcutaneous Basal-Bolus Administration of Insulin and Amylin in Adolescents with Type 1 Diabetes Decreases Postprandial Hyperglycemia; J Clin Endocrinol Metab. 94(5):1608–11 2009.

[7]  Insulin-plus-pramlintide artificial pancreas in type 1 diabetes – randomized controlled trial; ADA Oral Presentation 201-OR 2018.

[8]  Control of postprandial hyperglycemia in type 1 diabetes by 24-hour fixed-dose coadministration of pramlintide and regular human insulin: a randomized, two-way crossover study; Diabetes Care 41: 2346-52 2018.

[9]  Continuous Glucose Profiles in Healthy Subjects under Everyday Life Conditions and after Different Meals; Journal of diabetes Science and Technology 1:695-703 2007.

[10]  JDRF and amylin partner to investigate coformulating two hormones for treatment of type 1 diabetes; JDRF Press Release, May 10, 2011.

[11]  ADO09, A Co-Formulation of the Amylin-Analog Pramlintide and the A21G Human Insulin Analog, Lowers Postprandial Blood Glucose versus Insulin Lispro in Type 1 Diabetes; https://cslide.ctimeetingtech.com/attd2020/attendee/eposter/poster/258?q=pramlintide.

[12]  https://www.novonordisk.com/investors/rd_pipeline.html.

[13]  https://www.zealandpharma.com/longacting-amylin-analog

[14]  BZ043, a novel long-acting amylin analog, reduces gastric emptying, food intake, glycemia and insulin requirement in streptozotocin-induced diabetic rats; Peptides Epub ahead of print April 14 2019.

[15]  Efficacy of ITCA 650 vs Sitagliptin in Uncontrolled Type 2 Diabetes on Metformin; https://intarcia.com/media/company-presentations.html September 2017.