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Getting to Glucose Responsive Insulin – How “Smart” Will It Be?

By Emily Regier, Alexander Wolf, and Kelly Close

JDRF and Helmsley Charitable Trust workshop highlights future goals and expectations for glucose-responsive insulin.

Our team recently attended the JDRF-Helmsley Charitable Trust Glucose Responsive Insulin (GRI) Workshop in New York City. The highly interactive event brought together academic experts, researchers, industry, funding organizations, and patient advocates, including our own Kelly Close, to discuss the current state of the glucose responsive insulin field (also known as “smart insulin”). In theory, this next-generation insulin would work automatically in response to blood glucose: the higher the blood sugar, the more insulin is released or activated, and the lower the blood sugar, the less insulin is released or activated.

The long-term, “best case scenario” idea of the “perfect” smart insulin is very compelling for people with diabetes on insulin: one injection per day, blood sugar levels that stay in zone without hypoglycemia, no more carb counting, no more guessing what dose is correct, no more feeling frightened, and a much safer and less stressful life. The reality, as the leaders emphasized at this meeting, is that glucose responsive insulin (GRI) is still in its infancy, and development will likely proceed in steps: the first generation of these drugs may offer some, but not all, of the anticipated benefits.

Themes from the workshop

What will the holy grail GRI look like? How will it compare to the “first-generation” GRI product?

Speakers agreed that a perfect glucose-responsive insulin could eventually be an enormous game-changer for people with diabetes. In his talk to open the meeting, the highly respected Dr. Sanjoy Dutta (JDRF, New York, NY) noted that success in this area would lessen the complexity, burden, invasiveness, and danger of type 1 diabetes (and by extension, type 2 diabetes for those on insulin). He described an ideal GRI as a once-daily therapy that delivers the right amount of insulin at the right time in the right part of the body, leading to in-range blood sugars with little to no risk of hypoglycemia. Doesn’t that sound amazing!

However, much of the day’s discussion focused not on the “ideal” GRI, but rather the realistic first-generation products and what they might look like. While all participants agreed that a first-generation GRI would be a meaningful advance prior to development of the ideal product, there was some debate over exactly what that first product should look like. Dr. Dutta shared JDRF’s draft set of characteristics for the “ideal” vs. “first-generation” GRI, emphasizing that this list is by no means definitive. See below:

First Generation GRI

Ideal GRI

Helps with meals, but may still require basal insulin

No other insulin use required

Once or twice daily injection

Once daily injection

Glucose monitoring 2-3 times daily

Glucose monitoring 0-1 times per day

A1c reduction of 0.5%, similar effects to current insulins

A1c reduction of ~0.7%, superior to current insulins

~60% time in range (70-130 mg/dl). Others suggested that this range was too optimistic and proposed a target of 80% time in the 90-150 mg/dl range as a safer and more realistic alternative.

~80% time in range (70-130 mg/dl)

0-1 hypoglycemic events per week. Participants agreed that there needed to be more clarity around this definition and suggested that under five mild events per week might be more appropriate.

0-1 hypoglycemic events per month

Weight gain of ~0.5 kg (about one pound), comparable to current insulin therapies

Minimal weight gain

Reduced diabetes-related stress

Reduced diabetes-related stress

No severe product-related complications with chronic use

No severe product-related complications with chronic use

At the workshop, other proposed ideas for first-generation GRI products included (i) a combination of two different insulins, one for low glucose levels and one for high glucose levels; (ii) as many as five products approved for different populations (i.e., athletes vs. pregnant women vs. those with high hypoglycemia unawareness); (iii) a product approved only for type 2 diabetes; (iv) a post-meal GRI added on to existing basal insulin; and (v) a basal GRI added on to existing basal insulin.

How to manage patient expectations?

In her talk, Kelly Close of The diaTribe Foundation emphasized that hopes for GRI are very high, meaning companies and researchers need to set realistic expectations for people with diabetes and must focus on access to GRI as well. This is critical for avoiding disappointment with first-generation GRI products, which could be improvements over current insulins even if they have limitations (e.g., they only cover meals, require two shots per day). She presented survey data from diabetes market research company dQ&A (contact dQ&A on how to join their patient panel here) demonstrating that only 46% of patients are “very satisfied” with current insulins – and insulin has been around for almost 100 years!

Given such relatively low satisfaction, many are excited about smart insulin, and some people with diabetes even equate it with a cure. GRI developers must clearly communicate what the steps towards the “ideal” smart insulin will look like – what will first-gen products actually do?

Who will be able to access smart insulin?

“Do we want another diabetes product...that is only affordable for a few?” asked Dr. Irl Hirsch, who raised the issue of access in his presentation on GRI. He discussed whether diabetes research should prioritize innovative new solutions like GRI, when millions of people in the US and globally cannot even afford more basic insulin options. He concluded that it is worth proceeding with GRI, but the field needs to focus on demonstrating short- and long-term cost savings (e.g., reductions in severe hypoglycemia). Even if innovative insulins are developed and approved, if payers will not cover them, patients won’t have access.

Who is working on smart insulin?

Dr. Matthew Tremblay (Calibr, La Jolla, CA) provided an overview of the companies and academic groups with GRI candidates in development – with over 11 groups currently working on smart insulin projects. All of these projects are at a very early stage: one (Merck’s MK-2640) is in its first study in humans, and the others are all still being tested in animals. The groups all have very different approaches to GRI development, ranging from a smart insulin patch (UNC/NC State) to glucose-sensing nanoparticles (Monash University). All three major insulin companies – Sanofi, Lilly, and Novo Nordisk – are working on smart insulin as well, with Lilly recently acquiring smart insulin technology from the startup company Glycostasis in February 2016. We applaud JDRF, Sanofi, and the ADA Pathways Program for their funding support of many of these projects – read more on the JDRF/Sanofi smart insulin grant partnership here, and learn about the ADA Pathways Program here.

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