Our team recently attended the Carb DM Bay Area Diabetes Summit in our hometown of San Francisco, CA. The packed lecture hall at UCSF was abuzz with excitement from hundreds of patients with diabetes, families, caregivers, advocates, and healthcare providers – nearly 400 people registered ahead of time with more registering on-site the day of the summit (up from last year’s 380 attendees). While many of the children scurried off to the day-long diabetes camp run by Diabetes Youth Families (DYF), parents and other adults settled in for an illuminating series of lectures on the latest progress toward automated insulin delivery and new frontiers in the development of biological cures and preventive therapies for type 1 diabetes. Drs. Mark Atkinson (University of Florida, Gainesville, FL) and Fran Kaufman (Chief Medical Officer, Medtronic Diabetes, Northridge, CA) also provided a sobering yet inspiring look at diabetes care in developing countries in a joint keynote speech. The afternoon breakout sessions offered a chance to hear directly from the giants at the forefront of the march toward an artificial pancreas with a panel moderated by Tidepool’s Mr. Howard Look and featuring Bigfoot’s Ms. Jen Block, Stanford’s Dr. Bruce Buckingham, and Dr. Fran Kaufman. See below for our full report from the day.
Detailed Discussion and Commentary
Afternoon Breakout Sessions
A Comparative Look at Artificial Pancreas Systems
Francine Kaufman, MD (Chief Medical Officer, Medtronic Diabetes, Northridge, CA), Jen Block, NP (Bigfoot Biomedical, Milpitas, CA), and Bruce Buckingham, MD (Stanford University, Palo Alto, CA)
Medtronic’s Dr. Fran Kaufman, Bigfoot’s Ms. Jen Block, and Stanford’s Dr. Bruce Buckingham came together to discuss a variety of in-development automated insulin delivery systems. Ms. Block and Dr. Kaufman wished that the FDA could move a little faster, though as Dr. Buckingham pointed out, “it’s accelerated tremendously in the last two years.” Dr. Kaufman highlighted the tremendous investment Medtronic has made in the MiniMed 670G – ~$35-$40 million in clinical trials, an expected tens of thousands of pages in FDA submissions before this July – a reminder of the barriers to entry in this field. Notably, Medtronic hopes that the 670G’s cost will be close to comparable to current pump + CGM – that would be amazing news for patients. We were also glad to hear from Ms. Block that Bigfoot is on track to start pivotal studies in 2017, submit to FDA by the end of the year, and hopefully launch in 2018. Meanwhile, Dr. Bruce Buckingham pointed out the challenges of Bluetooth communication in closed loop research, something we hope will be fixed in commercial products. See key highlights immediately below followed by the outstanding panel discussion.
- Dr. Fran Kaufman highlighted that the pivotal trial for the MiniMed 670G hybrid closed loop system has completed (see our coverage). In the following panel, she shared Medtronic’s hope to provide the 670G at comparable cost to the cost of a separate sensor and pump system. This was the first we’ve heard on the pricing front and would be terrific news for patients if it is possible. Like her ATTD presentation, she mentioned that the company is embarking on a ~1,000 patient post-approval outcomes study and emphasized that this will be that largest trial ever completed of an automated insulin delivery system, costing tens of millions of dollars. Dr. Kaufman also shared that the FDA submission of the MiniMed 670G will consist of tens of thousands of pages of paper (!), highlighting the “arduous” journey to be first to market. That also underscores the challenges facing smaller companies trying to bring AID system to market. Interestingly, Dr. Kaufman commented that the regulatory requirements for next-gen AID systems are a bit unclear – will FDA require full clinical trials, bridging studies, or simply simulation? (“When we came up with the pink pump, it was a new submission.”) Also like her ATTD presentation, Dr. Kaufman highlighted that the 670G will include the option to temporarily set the system’s target to 150 mg/dl (rather than the usual 120 mg/dl target) if the patient is exercising, sick, traveling, or under other special circumstances.
- Bigfoot Biomedical’s Ms. Jen Block confirmed that the company plans to initiate pivotal trials in 2017 and submit the device to the FDA by the end of 2017 with the goal of a commercial launch in 2018. This was exactly in line with Jeffrey Brewer’s presentation in January. Ms. Block also reviewed the history of the company’s founding (see our initial interview) and the components in its own automated insulin delivery system: an Asante pump body (disposable) married to a custom built, durable, Bluetooth-enabled controller (no screen or buttons). The Bigfoot controller will talk to Dexcom CGM sensor and house the control algorithm, which enables the system to function in the absence of the mobile app. A Bigfoot smartphone app will serve as the window to the system and the user interface.
- Dr. Bruce Buckingham took a bigger picture view of automated insulin delivery landscape, drawing a contrast between systems that maintain the closed loop algorithm on the insulin pump itself and systems that store the algorithm on an Android or iPhone app that communicates with both the pump and the sensor. From his research experience, Dr. Buckingham noted that connectivity between different devices has always been an issue – Bluetooth, in his view, is not as reliable as he would like. It’s of course challenging to compare research platform devices with commercial products, so we’ll have to see if the ultimate commercial products are more reliable. We’d note that companies are pursuing various avenues – Medtronic has long taken the fully pump-integrated approach (algorithm + user interface on the pump), while Bigfoot will house the algorithm in the pump controller but use a smartphone app as the user interface. We assume Tandem and Animas will take an approach similar to Medtronic, while Insulet and TypeZero may do either. To our knowledge, no company plans to house the control algorithm in the smartphone alone.
- See our latest Automated Insulin Delivery competitive landscape here.
Mr. Howard Look (CEO, Tidepool, San Francisco, CA): The theme I hear is “wow, this is really hard, but there’s very good evidence that being on a closed loop system totally works.” My question is, why does it take 100,000 pages or until 2018? What is the thing you would change that would allow closed loop systems to get in people’s hands as quickly as possible?
Dr. Kaufman: It is a process. There is a need to show safety first and efficacy – does it really improve somebody’s outcome? We have had series of FDA meetings monthly for over a year. This has been priority for a lot of us. We would rather send a short memo than 100,000 pages, but I don’t disagree that we need a regulatory process. It’s been a good journey and we’re kind of there. I would hate to live in the US without any regulatory processes. It could be a little easier – if they could speed read very quickly, that would be nice – but we’re kind of there. As the first company, we’ve taken the brunt of a lot of unknowns, as we should. Perhaps the path won’t be quite as arduous for those coming up. The process will also push everyone to keep innovating. The FDA has said repeatedly “this is gen one and you better have gen two, three, and four in mind” because they want to see innovation.
Ms. Block: I agree with you, the process is really important. Many of you will be using these systems someday and the burden on us is to demonstrate that they’re both safe and efficacious. My biggest hope is that the process could be a little faster. On the outside looking in, there’s a strong desire to push further and go faster. On the inside, I see that the questions are reasonable and that they take time to show. All of these things take time; my biggest hope is that it would just be faster.
Dr. Buckingham: The reason it’s moving so fast at all is the patient advocacy that pushed hard on the government. The government can move slowly, but it can be moved. The process has gone so much faster – it’s accelerated tremendously in the last two years.
Q: When we’re talking about next-generation, does the FDA give a time stamp for companies on when the next-generation should be out?
Dr. Kaufman: They can’t demand anything from anyone. What isn’t clear to us is what will require another big clinical trial, what will require some simulation, and what will require a bridging study. Maybe there will be different interfaces for children, teens, and adults – we don’t know what they’ll require for that. When we came up with the pink pump, that was a long submission. If every time we want to innovate, we have to go through an arduous process, we’re all going to get stuck.
Q: How do you keep glucagon from going bad in the bihormonal devices?
Dr. Buckingham: There are a couple companies out there working on stable glucagon. One of them is Xeris, which puts in DMSO, which is non-aqueous solvent and has a shelf-life of more than a year. However, it will freeze in the fridge. There’s also a Danish company with glucagon [Zealand] that’s been modified so it’s stable in an aqueous solution with the same biological action.
Mr. Look: There are some companies like Medtronic and Bigfoot doing a single hormone system. Now some companies are doing bihormonal as well. Can you comment on the advantages and disadvantages of both?
Ms. Block: Dr. Buckingham pointed to research comparing insulin-only and insulin plus glucagon systems this morning. Insulin is well known and we have lots of experience delivering it, so it’s nice to start there.
Dr. Kaufman: It was a conscious decision to not go to glucagon at this point. Nobody has ever gotten glucagon every day in these quantities. It adds a complexity that we don’t feel is warranted – data shows that at this point, there’s not much of a difference between dual and single hormone. Move all that aside and just talk about cost – the 40%, 100% increase in cost, whatever it is. In my experience with the 530G, even with no price change whatsoever, a number of insurance companies said they didn’t feel comfortable covering it. What’s the added benefit of the added cost? The biggest threat to this whole field is who’s going to pay for it and what’s the cost going to be. We’re hoping there won’t be a difference between the cost of the 670G and what our sensor and pump cost now, even though we’re spending millions in clinical trials. We need to be aware of cost.
Dr. Buckingham: The fact that this is going to cost about the same is music to everyone’s ears. That said, glucagon is potentially a benefit in exercise situations. Also, it might be a benefit for someone with severe hypoglycemia unawareness, who maybe needs a glucagon pump.
Ms. Block: Until we have more experience with use, glucagon may be better for next-generation systems. We talked about some of the challenges of using a mobile app for the system and making upgrades to a system, but if you use a mobile app, you do have flexibility to do updates over the air.
Is there a Role for Non-Insulin Adjunct Therapy in Treating Adults with Type 1 Diabetes?
Marina Basina, MD (Stanford University, Palo Alto, CA)
Dr. Marina Basina (Stanford University, Palo Alto, CA) provided her take on various non-insulin therapeutic options for type 1 diabetes in a talk that echoed a recent debate between Drs. David Nathan and Anne Peters at Levine-Riggs. Given the recent concerns about DKA, Dr. Basina argued that SGLT-2 inhibitors should only be used in type 1 diabetes in the context of a clinical trial or at an institution with a strong protocol that includes routine serum and urine ketone testing. On the other hand, she described Sanofi/Lexicon’s phase 3 SGLT-1/2 dual inhibitor sotagliflozin as “most promising,” though she was careful to point out that its safety has not yet been proven in a larger population of patients with type 1 diabetes. Dr. Basina also reviewed the potential benefits and side effects of other type 2 diabetes medications that are often used off-label in type 1 diabetes, including metformin, pioglitazone, amylin, GLP-1 agonists, and DPP-4 inhibitors. She framed her presentation with a review of the physiology of insulin release and action as well as the significance of other hormones involved in glucose metabolism. She concluded that off-label prescriptions for type 1 diabetes are reasonable if there is a high likelihood of success in achieving better glucose control without weight gain or increased risk of hypoglycemia. That said, she emphasized that the current safety and efficacy data is scarce and also pointed out that the added cost of additional medications (particularly branded ones) needs to be taken into consideration as well. Overall, Dr. Basina’s presentation offered a comprehensive but fairly conservative take on the use of non-insulin therapies in type 1 diabetes and underscored the point that better, longer, and larger clinical trials are needed to more conclusively demonstrate the benefits of many of these therapies.
The Challenge of Type 1 Diabetes in the Developing World
Mark Atkinson, MD (Insulin for Life USA; University of Florida, Gainesville, FL)
Dr. Mark Atkinson (University of Florida, Gainesville, FL) focused on the barriers to insulin access in developing countries in his portion of this two-part keynote lecture. Dr. Atkinson applauded the remarkable progress in US diabetes care since the discovery of insulin in 1921, but he also drew attention to the 80,000-100,000 children around the world that he estimates lack consistent access to insulin. He also emphasized that this number does not include adults with type 1 diabetes or those with type 2 diabetes who need insulin. As expected, Dr. Atkinson highlighted the rising cost of insulin as a major contributor to this lack of access, but he was also quick to note that there are many complex barriers also at play. For instance, he pointed out that simply storing insulin in a cool environment is a major challenge in many parts of the world, as three quarters of the developing world does not have access to electricity and hence, refrigeration. He also discussed the tendency of many governmental health ministries to focus their resources on infectious rather than chronic diseases, though we hope this may change as infectious disease rates decline. Dr. Atkinson’s talk was primarily intended to raise awareness and provide context for the problem, but he also drew attention to Insulin for Life USA, a nonprofit he and his wife founded that collects extra insulin and other diabetes supplies to send to developing countries. Dr. Atkinson’s presentation provided a sobering contrast to the cutting-edge technologies and therapies discussed in the other sessions and served as a needed reminder that too many patients don’t have access to the most basic diabetes care. We applaud Dr. Atkinson for drawing attention toward this issue and providing an avenue for people to help.
Childhood Diabetes Around the World
Francine Kaufman, MD (Chief Medical Officer, Medtronic Diabetes, Northridge, CA)
Building on Dr. Atkinson’s presentation, Dr. Fran Kaufman’s (Chief Medical Officer, Medtronic Diabetes, Northridge, CA) portion of the joint keynote focused on her personal efforts to improve diabetes care in several developing countries. The inspiring, deeply personal presentation touched on a huge range of programs doing amazing work: Life for a Child, the IDF’s Youth Leadership Program, the AYUDA diabetes camps, the Haitian diabetes association FHADIMAC, and Medtronic’s work providing pumps and CGMs in Kazakhstan. Below are a handful of our favorite quotes from Dr. Kaufman’s presentation:
- “We’re leaving half of the world behind – we can’t forget them.”
- “I worked hard with their people. I needed to figure out what they need. If you think you can go in and solve all of their problems, you’re fundamentally crazy.”
- “With all that goes on, diabetes is hard for them to focus on. You’ve got to work within their system, with their people.”
- “We have so many advances. Our stream forward should be strong enough to bring the rest of the world with us, at least, if not absolute parity, to the point where they’re not dying.”
- “No child should die because they don’t have insulin and supplies or an educated provider or some modicum of care to keep them alive and healthy.”
Morning Plenary Sessions
Predictions for 2016
Steve Gitelman, MD (UCSF, San Francisco, CA)
Dr. Steve Gitelman (UCSF, San Francisco, CA) offered his perspective on the top advances in type 1 diabetes therapy to look forward to in 2016. He touched on diabetes technology with a quick mention of Tidepool’s Blip (an online diabetes management platform that integrates data from a variety of meters, pumps, and CGMs) and closed-loop projects, but the majority of the presentation was focused on early-stage biological cure approaches. On the beta cell replacement front, he emphasized that new stem cell differentiation protocols (like those from Dr. Doug Melton/Semma and Dr. Tim Kieffer/BetaLogics) have been a major advance but acknowledged that protecting the cells from autoimmune attack remains a key obstacle. As potential solutions, Dr. Gitelman highlighted cell encapsulation devices from ViaCyte and an MIT-based team led by Dr. Dan Anderson that is collaborating with the Melton group. Dr. Gitelman also spotlighted the new ADA/JDRF staging system for early-stage type 1 diabetes intended to facilitate earlier diagnosis and more efficient development of preventive therapies. He mentioned TrialNet’s oral insulin trial as a promising effort on the prevention front and highlighted two upcoming studies related to beta cell preservation in newly diagnosed patients: (i) a phase 2 study of an autologous Treg therapy in adolescents and (ii) a phase 1 study of Tregs and IL-2 in combination in adults. He also suggested that viruses may play a larger role in type 1 diabetes onset than we currently appreciate – a topic of seemingly endless debate in the field. Overall, our sense is that much of the excitement in the type 1 cure field in recent years has centered around cell replacement therapies, as immune modulation efforts face additional challenges related to the complex pathogenesis of the disease and the likely need for combination therapy.
The Scoop on Closed Loop: Bihormonal vs. Single-Hormone Artificial Pancreas Systems
Bruce Buckingham, MD (Stanford University, Palo Alto, CA)
Dr. Bruce Buckingham provided a comprehensive andfast-paced overview of the automated insulin delivery (AID) landscape. His presentation largely echoed his talk at ADA Postgrad and drew from data and his experiences with the Medtronic MiniMed 670G, UVA DiAs, Cambridge Florence D2A, and Boston’s Bionic Pancreas systems. His opening statement that Medtronic plans to release the 670G hybrid closed loop by April 2017 was met with a long round of applause from the packed lecture hall – it was clear from the energy in the room that the type 1 diabetes community has been looking forward to this for quite some time. [As of Medtronic’s 4Q15 update, an FDA submission of the 670G is expected before the end of this June, meaning a sub-12-month review is needed to hit this timeline – possible but definitely ambitious given the track record with the 530G.] Looking at the field overall, Dr. Buckingham especially praised the progress AID systems have made on nocturnal hyper- and hypoglycemia and showed off admirably flat nighttime CGM tracings from AID trials. However, he identified a host of variables that pose challenges toward fully automated insulin delivery during the day, including time delays, sensor accuracy, biologic variability of insulin, and activity. He also emphasized the real-world effect “dirty hands” can have on CGM accuracy – these examples are always very concerning and do make us wonder about real-world use of AID. In the future, Dr. Buckingham expects improvements in sensor accuracy (particularly factory-calibrated sensors; of course, FreeStyle Libre is already available OUS), innovations in infusion sets (including an integrated CGM sensor and infusion set), advances in algorithm adaptability, and progress toward faster-acting, more physiologic insulins.
Diabetes & Data: Getting the Most out of your Current Technology
Jenise Wong, MD, PhD (UCSF, San Francisco, CA)
Dr. Jenise Wong offered a practical, patient-centered look at the opportunities and challenges involved in making the most of diabetes data for at-home diabetes management. She highlighted the value of BGM, CGM, and pump data in aiding (i) real-time decisions for insulin dosage and (ii) retrospective data review to inform decisions about overall insulin regimen. She emphasized that adult endocrinologists expect their patients to engage in some degree of retrospective data review independently. Of course, that doesn’t happen in practice: Dr. Wong pointed to survey data that a minority of people with type 1 diabetes “routinely” download and review data (defined as downloading data ≥4 times in the past 12 months and reviewing the data ≥50% of the time). On the flip side, 69% of adults of type 1 diabetes and 44% of caregivers of those with type 1 diabetes (typically parents) never download their data. This should improve slightly as data downloading gets easier and more useful; however, it does beg a philosophical question – is the future of diabetes data in real-time decision support and automatic pattern recognition? Is it realistic to ever expect patients to download and review their historical data? Is that even useful relative to the potential of real-time notifications and automatic pattern identification in the background? Dr. Wong praised devices that wirelessly transmit and eliminate the need for unwieldy cables. On the software front, she highlighted Glooko and Tidepool for the ability to incorporate data from multiple different devices.
- Dr. Wong concluded her presentation with several practical tips for patients and caregivers to best understand their data. First and foremost, she advocated for all patients to try downloading and looking at their own data at home, perhaps using Tidepool’s Blip as a platform (which was originally piloted at UCSF). She suggested looking for and talking about data patterns as a family to get a better sense of how blood glucose might be affected by various lifestyle factors. Finally, she emphasized the importance of acknowledging the emotions associated with different numbers, be it stress, anger, pride, or happiness.
Progress Toward a Cure: A Citizen Scientist’s Overview
Karen Jordan (JDRF of the Greater Bay Area, San Francisco, CA)
Ms. Karen Jordan provided an easily digestible overview of the latest scientific advances toward a cure for type 1 diabetes. She began with an explanation of how new insights into the pathology of the disease have reframed treatment approaches. She explained that researchers are beginning to better understand the role of stressed beta cells in type 1 diabetes progression, which could open up new opportunities to restore immune regulation and beta cell function even after diagnosis. She also emphasized that the field is discovering new insights into the heterogeneity of the disease. On the treatment front, Ms. Jordan provided background and reviewed the current state of the field for artificial pancreas, beta cell encapsulation, glucose-responsive insulin, and beta cell restoration/regeneration. She also gave audiences a peek at promising frontiers on the prevention front, from TrialNet’s oral insulin trial to anti-CD3 to the gut microbiome. Finally, she touched on the idea of a “reverse vaccine” to promote regulatory T cells (Tregs) that is in development from REGiMMUNE in collaboration with JDRF and Pfizer. Ms. Jordan’s presentation served as an excellent reminder of the flurry of research interest in the type 1 diabetes cure field and the importance of keeping patients and the public informed in an engaging, understandable way.
-- by Helen Gao, Adam Brown, Emily Regier, and Kelly Close