April 29, 2016; New York, NY; Full Report – Draft

Executive Highlights

Our team had the wonderful opportunity to attend the JDRF-Helmsley Charitable Trust Glucose Responsive Insulin (GRI) Workshop last week in New York, NY. The highly interactive event brought together academic experts, JDRF-funded investigators, industry representatives, and patient advocates to discuss the current state of the GRI field, the key challenges to address going forward, and the target profile of both a first-generation and an ideal product. We found the discussion both sobering and encouraging. It underscored the fact that this field is truly in its infancy and that development of an ideal GRI will be an iterative process, with the first generation of these drugs offering some, but not all, of their anticipated benefits. We were inspired by the passion and thoughtfulness of this group, particularly their commitment to keeping patients at the center of the discussion and focusing on issues like access even at this very early stage. We applaud JDRF for hosting this informative workshop and for their longtime leadership in the GRI field, most recently through an expanded collaboration with Sanofi that will provide $4.6 million in funding over three years for four GRI-related products. Read on below for our top ten highlights from the meeting.

1. Dr. Michael Strano (MIT, Cambridge, MA) reviewed the state of the science in the GRI field, dividing current efforts into four basic “cases”: (i) biodegradable hydrogels; (ii) glucose-binding moiety gels; (iii) glucose-responsive hydrogels; and (iv) modified free circulating insulins.

2. Dr. Matthew Tremblay (Calibr, La Jolla, CA) provided a valuable overview of the companies and academic groups with GRI candidates in development. Merck is the only company with a candidate in clinical development, but the early-stage preclinical pipeline is fairly crowded.

3. Speakers agreed that a perfect glucose-responsive insulin could eventually be an enormous game-changer for patients with diabetes.

4. Much of the day’s discussion focused on the target product profile for a first-generation GRI. JDRF’s broad target product profile includes A1c non-inferiority with more time in range and less hypoglycemia vs. standard of care.

5. Ms. Kelly Close (The diaTribe Foundation, San Francisco, CA) emphasized the need to bridge the gap between the sky-high patient expectations for a GRI and what will be possible with a first-generation product.

6. The main safety concerns participants raised related to GRI were hypoglycemia, immunogenicity, and biocompatibility.

7. Key hurdles related to research logistics included the need for studies in large animal models and core research facilities to validate initial results.

8. Looking down the road, participants anticipated several regulatory issues related to GRI, particularly a lack of understanding at the FDA about the need for new insulins.

9. “Do we want another diabetes product with minimal uptake for a decade that is only affordable for a few?” Dr. Irl Hirsch (University of Washington, Seattle, WA) delivered a characteristically passionate presentation about the importance of access in an era when many patients struggle to afford current insulin options.

10. There was a clear consensus around the need to attract interest in GRI from outside the core diabetes community, including from venture capitalists and researchers in other disciplines.

Top Ten Highlights

1. Dr. Michael Strano (MIT, Cambridge, MA) reviewed the state of the science in the GRI field, dividing current efforts into four basic “cases”: (i) biodegradable hydrogels; (ii) glucose-binding moiety gels; (iii) glucose-responsive hydrogels; and (iv) modified free circulating insulins. In case one, an enzyme (typically glucose oxidase) reacts with glucose, leading to a pH change that causes the hydrogel to degrade and release insulin. In case two, glucose can bind to specific moieties on a hydrogel that causes it to release cross-linked insulin. Dr. Strano described case three as a hybrid of the first two: glucose reacts with an enzyme, and the resulting pH change causes the hydrogel to expand and release insulin. Case four is the most distinct from the other approaches; it involves an inactive form of insulin that becomes active when exposed to glucose. Dr. Strano argued that all four cases can be simplistically described by two chemical equations: (i) glucose + receptor à active GRI and (ii) active GRI à insulin. It is therefore possible to use basic models based on known glucose and insulin dynamics in the human body to define rate constants and equilibrium constants for those equations that allow a GRI to operate within desired parameters. Later in the morning, Dr. Zhen Gu (UNC/North Carolina State University) reviewed advances in development of GRI formulations, including his group’s efforts. Dr. Gu was a 2015 ADA Pathway grant recipient and published promising results for his smart insulin patch in a mouse model of type 1 diabetes last July; he was also one of four researchers to receive funding under the recent JDRF/Sanofi GRI collaboration.

2. Dr. Matthew Tremblay (Calibr, La Jolla, CA) provided a valuable overview of the companies and academic groups with GRI candidates in development – see the table below for his list.

Table 1: Glucose-Responsive Insulin Competitive Landscape

3. Speakers agreed that a perfect glucose-responsive insulin could eventually be an enormous game-changer for patients with diabetes. In his talk to open the meeting, Dr. Sanjoy Dutta (JDRF, New York, NY) noted that success in this area would accomplish many of JDRF’s overall aims of lessening the complexity, burden, invasiveness, and danger of type 1 diabetes; the benefits would of course apply to type 2 diabetes as well, presumably. He described an ideal GRI as a once-daily therapy that delivers the right amount of insulin at the right time in the right tissue, eliciting euglycemia. In her presentation later in the day, our own Ms. Kelly Close (The diaTribe Foundation, San Francisco, CA) agreed that many patients consider smart insulin the holy grail of diabetes care, and that what they are envisioning is a once-daily or once-weekly therapy that can control glucose perfectly with no work from the patient. The meeting organizers outlined one potential target product profile for an ideal GRI (injected once daily, superior A1c reductions vs. current standard of care, ~80% time in range, <1 hypoglycemic event per month, minimal weight gain – see the appendix for more details), though most of the discussion understandably focused on the target profile for a first-generation product. We expect that the field will gain a much better sense of both what is ideal and what is achievable for a GRI once a first-generation product is closer to reaching the market.

4. Much of the day’s discussion focused on the target product profile for a first-generation GRI. The organizers provided an outline of one potential product, though Dr. Dutta emphasized that this was by no means intended as a definitive set of criteria. Full details of that proposal are provided in the appendix; broadly, such a candidate would be non-inferior to current options in terms of A1c, offer more time in range and less hypoglycemia, be dosed once or twice daily, and require glucose monitoring two to three times per day. In her talk focused mainly on patient expectations, Ms. Close suggested that while hopes in this area are sky-high, even incremental innovations could make a huge difference for patients and providers. She cited the closed loop field as an analogous case – incremental improvements like predictive low glucose suspend have been very clinically meaningful even though they fall short of fully automated insulin delivery. While all participants agreed that a first-generation GRI will be a meaningful advance that still falls far short of the ideal product, there was a significant amount of debate over exactly what that first product should look like. Proposed ideas included (i) a combination of two GRIs, one for low glucose levels and one for high glucose levels; (ii) as many as five products approved for different sub-populations; (iii) a product approved only for type 2 diabetes; (iv) a postprandial GRI added on to existing basal insulin; and (v) a basal GRI added on to existing basal insulin. See the appendix for more details on the discussion around each of these options.

5. Ms. Close emphasized the need to bridge the gap between the sky-high patient expectations for a GRI and what will be possible with a first-generation product. She presented survey data demonstrating a real unmet need for new insulin options – only 46% of patients are very satisfied with current insulin therapies, which is fairly astounding for a lifesaving drug that has been around for almost 100 years. Given the inadequacy of current options, many patients have pinned enormous hope on the idea of a smart insulin, which many essentially equate with a cure. Ms. Close stressed that while it might be obvious to those in the GRI field that there will be early failures and that progress will come through iterative improvements, it is far from obvious to the average patient with diabetes. It is therefore crucial for stakeholders to clearly communicate where the gaps are and what the incremental steps will look like, and to keep patients’ and providers’ needs in mind when designing those interim products. She turned to the diabetes technology field for examples of both the successes and challenges of incremental innovation. Patient satisfaction with pumps and CGM has gone up considerably since the first products were introduced, but uptake remains limited, partly because the system does not provide good incentives for providers to take the time to effectively train patients on the technology. Dr. Irl Hirsch (University of Washington, Seattle, WA) echoed many of these sentiments during his presentation, arguing that despite the significant improvements in diabetes care over the past few decades, the current treatment paradigm is still unacceptably difficult and requires far too much effort from patients. He suggested that the closed loop could itself be an incremental step on the road to a GRI: patients could first add a basal GRI to a closed-loop system, then add a prandial GRI, and then switch to a GRI alone.

6. The main safety concerns participants raised related to GRI were hypoglycemia, immunogenicity, and biocompatibility. A breakout session focused specifically on safety concluded that a GRI must be “hypo-safe,” with no risk of extreme hypoglycemia and no potential for catastrophic insulin release. It also must be able to adapt to the variability in human physiology caused by exercise, overeating, illness, etc. On immunogenicity, the main conclusion was that antibodies that neutralize insulin action would be an absolute no-go, as patients might not even be able to switch back to other insulins if the GRI stopped working. Some participants also suggested that using native insulin might be more desirable because of the lower risk for immunogenicity. Biocompatibility was cited as another important consideration, especially for the hydrogel-based approaches. Other potentially important factors included drug clearance and the impact of depots and metabolites of the technology. While these safety considerations are crucial, we were glad to hear participants acknowledge that insulin is inherently an unsafe drug and that the diabetes community would likely be willing to accept some level of risk for a product that provides significantly greater efficacy and quality of life compared to current options.

7. Key hurdles related to research logistics included the need for studies in large animal models and core research facilities to validate initial results. A number of participants noted that translating results for GRI candidates from mouse models of type 1 diabetes to humans will likely be difficult for a number of reasons; for example, rodents are much less prone to hypoglycemia and there are significant differences in their subcutaneous space compared to humans. Conducting studies in large animals like pigs will therefore be an important step in the GRI development process, which can pose challenges for academic investigators who do not have access to those models. Participants suggested that this could be one use for a core research facility funded by pharmaceutical companies, venture capitalists, and/or organizations like JDRF. Another proposed purpose for such facilities was external validation of initial results from academics. As one participant noted, all scientific disciplines are currently struggling with the issue of poor reproducibility, and it will be crucial to replicate preclinical results for GRI candidates from individual labs before advancing them to clinical trials.

8. Looking down the road, participants anticipated several regulatory issues related to GRI, particularly a lack of understanding at the FDA about the need for new insulins. In terms of clinical endpoints, the consensus seemed to be that while A1c may not be the best metric of success for a GRI, it will almost certainly be the one that is most valued by the FDA. Participants did generally agree that demonstrating A1c non-inferiority vs. standard of care could be sufficient for approval in the context of additional benefits. There was also agreement that hypoglycemia would be a highly clinically relevant endpoint for a GRI, but the lack of clarity around definitions and measurements in this area repeatedly emerged as an obstacle. One participant also noted that severe hypoglycemia is quite uncommon in clinical trials, to the point that one would need to enroll 5,000 patients to have sufficient power to detect a 30% reduction. This was one of several issues that led to a discussion of the gaps between clinical trials and real-world practice, where severe hypoglycemia is quite common. The lack of understanding at the FDA about the unmet need for new insulins also sparked plenty of passionate commentary from the group. A Lilly representative who worked on the submission team for failed basal insulin peglispro asserted that “the FDA perceives we have all the insulins we need.” Dr. Douglas Muchmore (Kinexum, Harpers Ferry, WV) echoed that sentiment, noting that someone at the FDA once argued to him that “insulin is insulin is insulin.” We see this as an area where patient advocates can play a very meaningful role in helping the FDA understand the daily burden of managing diabetes and the inadequacies of current insulin options.

9. “Do we want another diabetes product with minimal uptake for a decade that is only affordable for a few?” Dr. Irl Hirsch raised the issue of access in a characteristically passionate presentation about the clinical considerations around GRI. He even posed the question of whether it is ethical for the field to focus resources on developing GRI candidates when so many people cannot even afford current insulins. He ultimately concluded that it is worth proceeding, but he emphasized the need to be strategic and focus on developing products with demonstrated short- and long-term cost-effectiveness that can appeal to payers. Ms. Close touched on similar themes in her presentation, suggesting that a GRI with a strong value proposition for payers could help address some of the concerns about the rising cost of insulin. On the other hand, Dr. Hirsch noted that the usual rules – in which prices of new drugs go down and production goes up over time – have not applied in the case of new biologics for diseases like rheumatoid arthritis and psoriatic arthritis. He is therefore fairly pessimistic about achieving an affordable price for a GRI, at least initially. Dr. John Amatruda (John Amatruda Consulting LLC, New York, NY) agreed that the cost will likely be high in the US absent dramatic policy changes, which he sees as unlikely. Like Dr. Hirsch, he emphasized the importance of demonstrating a clear value proposition for payers; he suggested that demonstrating an adherence advantage vs. MDI could be one effective way to do so. We were encouraged by this focus on access at the earliest stages of GRI development and hope this continues once development is in the hands of large companies. We expect that payers would be willing to cover a truly disruptive GRI even at a high list price if the manufacturer could demonstrate a clear long-term value proposition. Issues could arise, however, if government payers simply do not have enough resources to cover the cost for all eligible patients (as is the case for the hepatitis C drugs that have sparked so much recent controversy) or if payers impose strict eligibility criteria in an effort to reduce overall costs (as they have for PCSK9 inhibitors).

10. There was a clear consensus around the need to attract interest in GRI from outside the core diabetes community. There was some debate over the role of venture capitalists in funding GRI research. Dr. Amatruda and several JDRF representatives argued that they should be an essential part of the equation, while Ms. Close expressed some skepticism about their level interest in diabetes and patient outcomes. She suggested that appealing to venture philanthropists or large foundations might be a more successful approach. Participants also discussed ways to attract interest from researchers in disciplines like chemistry or engineering who can make valuable contributions to the field but have likely had little exposure to diabetes. Several people also noted that even researchers working on GRI often have little sense of what day-to-day life with diabetes is like. Suggestions to address these knowledge gaps included GRI workshops targeted at students and postdocs at ADA or other large conferences, joint fellowships with the American Chemical Society or other organizations outside diabetes, or joint industry-academic postdoctoral programs focused on GRI. Ms. Close also noted that social media activity has been a major driver of interest and innovation in the closed loop field and that it might behoove investigators in this field to be a bit less publicity-shy about their data. 

Appendix

JDRF Draft Target Product Profile for an Ideal GRI

• Indicated for all insulin-dependent diabetes
• No other insulin use required
• Subcutaneous injection once daily
• Titration once daily
• Glucose monitoring once or less per day
• A1c reduction of ~0.7%, superior to standard of care comparator
• ~80% time in range (fasting plasma glucose 70-130 mg/dl)
• <1 hypoglycemic event per month
• Minimal weight gain
• Reduced diabetes-related stress based on patient-reported outcomes from PAID questionnaire
• No severe complications with chronic use

JDRF Draft Target Product Profile for a First-Generation GRI

• Indicated for all insulin-dependent diabetes
• May require concurrent use of basal insulin
• Subcutaneous injection once or twice daily
• Titration once daily
• Glucose monitoring two or three times daily
• A1c reduction of ~0.5%, non-inferior to standard of care comparator
• ~60% time in range (fasting plasma glucose 70-130 mg/dl). Others suggested that this target range was too optimistic and potentially dangerous and proposed a target of 80% time in the 90-150 mg/dl range as a safer and more realistic alternative.
• <1 hypoglycemic event per week. Participants agreed that there needed to be more clarity around the definition of this parameter and suggested that <5 mild events per week might be more appropriate.
• Weight gain of ~0.5 kg, comparable to current insulin therapies
• Reduced diabetes-related stress based on patient-reported outcomes from PAID questionnaire
• No severe complications with chronic use

Other Ideas for First-Generation GRI

• A combination of two GRIs, one for low glucose levels and one for high glucose levels. Dr. Dutta proposed this idea during a discussion about the technical difficulty of developing a GRI that works within the entire range of human glucose levels. Other participants agreed that this could be a particularly good solution if the scientific community decides to “divide the problem,” as each of the four approaches outlined by Dr. Strano has strengths and weaknesses at the higher and lower limits of glucose levels.
• Several different GRIs for sub-populations of type 1 diabetes, including those at high risk of severe hypoglycemia, those with a long duration of disease and low hypoglycemia awareness, pregnant women, and young athletes. The idea was that the reimbursement proposition might be more appealing with these clearly defined populations, even though the total number of patients would be lower.
• A product approved only for type 2 diabetes. This would be a somewhat surprising turn of events given that so much of the innovation in this area has been driven by JDRF. The argument was that the FDA would have fewer concerns about safety in this more “forgiving” population that would presumably not be relying entirely on the GRI and would have a lower risk of hypoglycemia. This logic was fairly compelling to us, though it could spark some patient backlash given the arguably greater unmet need and higher patient expectations in the type 1 diabetes community.
• A postprandial GRI added on to existing basal insulin. This idea was based on the argument that the newest basal insulin analogs (Novo Nordisk’s Tresiba [insulin degludec] and Sanofi’s Toujeo [insulin glargine U300]) are already close to optimal and that much of the burden of diabetes management (weight gain, hypoglycemia, frequent injections) is related to mealtime insulin. In addition, a GRI designed only to address postprandial excursions could have a fairly high lower bound of action, hopefully leading to fewer concerns about hypoglycemia.
• A basal GRI added on to existing prandial insulin. Dr. Hirsch was the main proponent of this idea. He argued that controlling postprandial excursions will likely be the “Achilles heel” of GRI development and that it could be smart to ensure earlier success by aiming for a basal-only product initially. He suggested that such a product could make a meaningful difference for patients by improving parameters like time in range and exercise tolerance and could provide a bridge between the device-based closed loop and full GRI treatment. However, Dr. Amatruda countered that a basal-only GRI would be a less attractive proposition for companies and payers than a prandial product due to the much greater unmet need for new prandial insulins.

-- by Emily Regier and Kelly Close