July 8-12, 2015; Orlando, FL; Day #3; Highlights – Draft

Executive Highlights

Greetings from Orlando, where the Friends for Life agenda is heating up along with the temperature – it hit over 95 degrees today! The biggest highlight of the conference’s first day of sessions was Dr. Ed Damiano’s packed unveiling of the iLet: a prototype, fully integrated, dual-chamber Bionic Pancreas device. There must’ve been 300 people in the audience – absolutely packed, wall-to-wall. We’ve got all the pictures and design details below. Other notable items included a talk from dQ&A’s Richard Wood and Close Concerns’ Adam Brown for parents and patients on selecting the right diabetes device; a well-received lecture from world-renowned celiac researcher Dr. Alessio Fasano on autoimmune disease and the microbiome (!); and an update on the visionary nPOD initiative, an area that has been receiving increasing attention from us. The day concluded with the lively Novo Nordisk-sponsored Friends and Family Banquet, always one of our favorite events of this conference. We include our highlights below. Stay tuned for more from FFL in our final report, including our take from our f-a-v-o-r-i-t-e session every year at FFL, the faculty poster session where so many patients get to rub shoulders with so many incredible researchers.

Top Five Highlights

1. Dr. Ed Damiano’s annual update on the Bionic Pancreas did not disappoint, sharing for the first time the team’s own custom-built, dual-chamber, prototype pump and Tidepool-designed touchscreen user interface for a fully integrated commercial version of the Bionic Pancreas. This presentation received several excited ovations from attendees, and Twitter was a frenzy afterwards.

2. dQ&A’s Richard Wood and Close Concerns’ Adam Brown talked with parents about how to choose their next diabetes device. Parents seemed especially daunted by choosing a pump, and this session reminded us of how much more difficult that decision is becoming – and has always been! This session used information from dQ&A’s surveys, which has incorporated well over 1,000 ratings from pump users alone over the past several years and hundreds of CGM users. More recent inputs into dQ&A include type 1 patients on SGLT-2 inhibitors – off label – as well as patients using Afrezza and patient views on the artificial pancreas.

3. World-renowned celiac researcher Dr. Alessio Fasano (MGH, Boston, MA) delivered a very interesting and very well-received talk on a common framework for autoimmune diseases based on gut permeability and the microbiome. We are always incredibly impressed with the sophistication of audience members at this meeting.

4. Dr. Alberto Pugliese (DRI, Hollywood, FL) provided an update on the impressive nPOD initiative and its potential to uncover new therapeutic approaches for type 1 diabetes.

5. The Novo Nordisk-sponsored Family and Friends Banquet provided a lively end to the day, complete with Disney remixes, light-up costumes, a heartwarming slide show, and a packed dance floor. Renowned diabetes advocate (and now SVP of Member Experience at Livongo) Manny Hernandez won the highly acclaimed “distinguished service” award.

Honorable Mention: Adam shared his 10 Tips for Living Well with Type 1 to the Friends for Life 15-18 year-old teens – they loved hearing about Adam as a teen and how his life has evolved given his big-time education with diabetes. You can see his slides here.

Top 5 Highlights

1. Dr. Ed Damiano’s annual update on the Bionic Pancreas did not disappoint, sharing for the first time the team’s own custom-built, dual-chamber, prototype pump and user interface for a fully integrated commercial version of the Bionic Pancreas. We absolutely love that each year, Ed delivers among the MGH/BU’s biggest news at this meeting, which is 100% patients, patient advocates, and families. He also tends to be willing to stay long into the night answering questions and serving as the much-loved faculty that he’s been for so many years. It’s cleverly called, “iLet,” borrowing from iSomething devices and the “ISLETS” of Langerhans. As you would imagine, the session was completely packed, and we have all the pictures and details below. The still-prototype, integrated device is about the size of an iPhone 6, about 2.5 times as thick, uses a resistive touchscreen (a bit hard to press in this prototype version, similar to other first-gen devices, including the Abbott Libre), includes built-in Dexcom and algorithm integration, and separate pump chambers for pre-filled insulin and glucagon cartridges. The iLet’s user interface was designed by the Tidepool team – fantastic, as this comes with big-time credibility (especially considering Tidepool’s Howard Look and his team were honored yesterday by none other than the White House!) and was very user-friendly in our run through it. The hope is ultimately to improve the device by making it smaller and enhancing the touchscreen over the next nine months (more details below on the plans). The current timeline is: a human factors and bridging study with a custom-designed infusion set and the Dexcom G5 transmitter in Q2-Q3 2016; a two-phase pivotal study with Xeris glucagon to at 16 centers (see our detailed notes for where!) from 1Q17 to 1Q18; and an FDA PMA review (including a chronic indication for Xeris) to overlap from 4Q17 to 3Q18. This is on par with what we heard at GTC Bio in April, though here’s one difference: the FDA review is now one quarter longer. Two glycemic set point studies with the current iPhone-driven research platform will still start in August at Stanford (insulin-only version – this will be fascinating and we’re so excited that the Dr. Bruce Buckingham and Dr. Trang Ly-led team will be leading this) and MGH (insulin-only vs. insulin+glucagon). As a reminder, these set point studies will allow users to set the algorithm's aggressiveness by targeting different glucose values (e.g., 100 mg/dl [more aggressive] vs. 140 mg/dl [more conservative]). Dr. Damiano and his team received thunderous applause and a massive line immediately formed in the exhibit hall to play with the device and to chat with Dr. Damiano. For now, it’s unclear who is building the iLet and how it will be commercialized, but we assume details will emerge over time. See much more detail below on the device’s specifics, rationale for building it, planned improvements, pivotal trial, funding needed, and pictures.

2. dQ&A’s Richard Wood and Close Concerns’ Adam Brown talked with parents about how to choose their next diabetes device. The talk discussed diabetes device satisfaction scores and highlighted the key factors to consider when choosing a meter, a pump, and a CGM. Both Richard and Adam emphasized that individualization is key (answer the Question: “What is important to you?”), especially because all devices have pros and cons, and features can appeal much differently depending on what a family and patient needs/wants at that time. Parents seemed especially challenged by choosing a pump, and this presentation reminded us of how much more difficult that decision is becoming. Adam and Richard provided tables to break down the key features, drawbacks, and upcoming pipelines of the main pumps and CGMs in the US – you can find these in the detailed commentary below. Adam lamented that buying a pump is as big a decision as buying a car, though families often feel like they cannot “try before they buy” – this was greeted by enthusiastic nods in the audience. We had been fans of the Asante Snap free trial program and wonder what else companies could do to help patients get a real feel for a device before committing to it – though we understand challenges with this and in fact had been very surprised that Asantae had been willing to take on the costs of executing this. Indeed,  the economics can be challenging – while Insulet has also done a great job with its demo pod program, this is much easier to do with a disposable business model. Parents in the room were also interested in the remote monitoring products, particularly cellular-connected meters that send notifications, Dexcom Share, and MiniMed Connect. Similar to other FFL session, there was tremendous enthusiasm for Dexcom and the Share system, which has really resonated with parents and seemed to meaningfully alter many family dynamics – though we’re still figuring out and listening to patient feedback on parents on SHARE always receiving numbers! (Stay tuned for popular blogger Kerri Sparling writing about this in her next column in diaTribe – if you’d like this sent to you directly, let us know!)

3. World-renowned celiac disease researcher Dr. Alessio Fasano (Massachusetts General Hospital, Boston, MA) delivered a well-received talk on a common framework for autoimmune diseases based on gut permeability and the microbiome. Yes, this is a pretty complex topic for a patient conference but there were plenty of folks interested in listening to this! Describing the process as akin to a battle, he explained that when an “enemy” penetrates the gut epithelium and the immune system deploys its forces, the fighters can either remain on the original battlefield (celiac disease) or travel elsewhere (type 1 diabetes). Either way, the early steps and the collateral damage caused by chronic inflammation are conceptually similar. While it is unfortunately not possible to halt the vicious cycle at step one in type 1 diabetes as it is with celiac disease, Dr. Fasano suggested that interfering at step two – gut permeability – is a “tangible possibility.” The most passionate portion of his talk came near the end, when he discussed the recently discovered role of the gut microbiome in modulating the risk of autoimmunity (“I’ve been studying this for 30 years and I didn’t see this coming”). He noted that while humans are the most sophisticated species on the planet, “genetically we’re at the bottom” with only 25,000 genes. However, the human microbiome constitutes a “parallel civilization” containing 100,000 more genes than us, and Dr. Fasano believes that harnessing that much more dynamic genome will be “the key to unleash the war against autoimmunity.” While the knowledge base is fairly limited at this point, he argued that there is “strong circumstantial evidence” that factors in the first three years of life (e.g., vaginal delivery, breastfeeding, antibiotic use) can act through the microbiome to set a threshold for immune attack. While this field remains in its infancy, the interest in the room was palpable – we are particularly glad to see more attention paid to the potential links between the microbiome and type 1 diabetes, as the (equally intriguing) connections to type 2 diabetes and obesity have generally been a larger focus.

4. Dr. Alberto Pugliese (Diabetes Research Institute, Hollywood, FL) discussed nPOD’s potential to uncover new therapeutic approaches for type 1 diabetes. nPOD (Network for the Pancreatic Organ Donor with Diabetes) is a JDRF-sponsored initiative that facilitates collaborative research with tissue samples from organ donors with type 1 diabetes or islet autoantibodies. As Dr. Pugliese explained, the bulk of our knowledge about type 1 diabetes pathophysiology has come from animal studies, which cannot effectively answer many questions about the human disease process – the litany of promising preclinical therapies that have failed to translate to humans is likely a consequence of this. He presented a wide range of findings demonstrating how nPOD-supported research has already expanded our understanding of the disease. For example, the presence of inflammation in samples from patients with well-established diabetes suggests that the autoimmune process may be more chronic than is typically assumed, and therefore there may be a larger window for intervention. Other studies identifying disturbances in various cellular metabolic pathways have helped explain the paradox of patients with a substantial number of insulin-positive islet cells but no detectable beta cell function. The enormous challenges of this field were clear throughout the presentation: the possibility of a single therapy that can fully address the pathophysiology of type 1 diabetes seems more and more remote as more contributing pathways are discovered, and there remains a huge gap between the supply and demand of human pancreatic tissue for research. However, we agree that these findings could certainly reveal novel therapeutic targets that could be amenable to combination approaches. We are also incredibly impressed with nPOD’s emphasis on data-sharing and collaboration – we would love to see that become more of an accepted model in academic research.

5. The Family and Friends Banquet provided a lively end to the day – it’s not every conference where the dress code for dinner includes light-up wings and tiaras! After parents and children enjoyed dinner with remixes of classic Disney songs playing in the background, several organizers and longtime FFL attendees waxed nostalgic about the event’s 16-year history and recounted stories of how they became involved. We were thrilled to see Mr. Manny Hernandez take the stage to accept the Jeff Hitchcock Distinguished Service Award – an very well-deserved honor for the founder of the Diabetes Hands Foundation, a now longtime diabetes non-profit committed to making sure that no patient with diabetes ever feels alone. Watching four incredibly creative videos produced by children with the aim of explaining type 1 diabetes in one minute was another highlight of the evening: we have never seen a four-year-old quite so knowledgeable about pumps and CGM. Of course, such a Disney-heavy night would not be complete without multiple selections from “Frozen,” including a diabetes-themed take on “Do You Want to Build a Snowman” and a heartwarming slide show from the conference to the tune of “Let It Go.” Kudos to CWD and Novo Nordisk for putting on such a successful event – the dance floor was still packed by the time our team called it a night – of course, we were all busy getting ready this report for all of you!

Honorable Mention: Adam Brown, Close Concerns’ head of diabetes technology and digital health shared his Top 10 Tips for Living Well with Type 1 with the 15-18 year-old teens. You can see his slides here. A group of over 100 teens were impressively engaged and the Q&A that followed was rich with group-wide problem solving: “My younger brother has diabetes and I don’t know how to help. What should I do?” (we are particularly sympathetic on the sibling front) and “I just keep forgetting to check my blood sugar throughout the day. What do you recommend?” The latter question was Adam’s favorite – this patient traveled all the way from India to FFL, and left the room strongly considering a CGM trial. We hope he is able to afford it – we are also especially sympathetic to every patient in India, where there is absolutely no safety net and where all costs associated with diabetes are taken on by patients and their families.

Detailed Discussion and Commentary

The Bionic Pancreas

The Bionic Pancreas

Ed Damiano, PhD (Boston University, MA)

Dr. Ed Damiano’s annual update on the Bionic Pancreas did not disappoint, sharing for the first time the team’s own custom-built, dual-chamber, prototype pump and user interface for a fully integrated commercial version of the Bionic Pancreas. It’s cleverly called, “iLet,” borrowing from iSomething devices and the “ISLETS” of Langerhans – what a fabulous name. The session was completely packed, and we have all the pictures and details below. The still-prototype, integrated device is about the size of an iPhone 6, about 2.5 times as thick, uses a resistive touchscreen (a bit hard to press in this prototype version, similar to how the Abbott Libre touch-screen buttons are a bit hard to press – at least compared to the iPhone), includes built-in Dexcom and algorithm integration, and separate pump chambers for pre-filled insulin and glucagon cartridges. The iLet’s user interface was designed by the Tidepool team and was very user friendly in our run through it. The hope is ultimately to improve the device by making it smaller and enhancing the touchscreen over the next nine months – ideally, it will resemble the iPhone 3 in screen size (~30% smaller) and use a capacitive touchscreen e-ink display (similar to the Amazon Kindle). Once the design is locked down, the plan is to run iLet in a human factors and bridging study with a custom-designed infusion set and the Dexcom G5 transmitter in Q2-Q3 2016. The hope is for a two-phase pivotal study with Xeris glucagon to take place at 16 centers across the United States from 1Q17 to 1Q18, and an FDA PMA review (including a chronic indication for Xeris) to overlap from 4Q17 to 3Q18. This is on par with what we heard at GTC Bio in April, though the FDA review is now one quarter longer. To answer the last major research question, the plan is still to conduct two glycemic set point studies with the current iPhone driven research platform starting this August – an insulin-only version at Stanford (August-October) and an insulin-only vs. insulin+glucagon version at MGH (August 2015-March 2016). As a reminder, these set point studies will allow users to set the algorithm's aggressiveness by targeting different glucose values (e.g., 100 mg/dl [more aggressive] vs. 140 mg/dl [more conservative]). Dr. Damiano and his team received thunderous applause and a massive line immediately formed in the exhibit hall to play with the device and to talk to the very-popular Dr. Damiano (he’s incredibly responsive to patients and families and it always seems he would talk as long into the night as patients requested – which is LONG into the night! We’ve seen some incredibly accessible faculty at FFL and Dr. Damiano is among the very most responsive.). For now, it’s unclear who is building the iLet and how it will be sold, but we assume details will emerge over time. The team is looking to raise $4.5 million over the next 18 months to get to the pivotal study, which itself will cost $14 million. They have received a “fundable” score on the major NIH artificial pancreas grant initiative, but it’s unclear how much funding (if any) they will receive. More below!

• Dr. Damiano discussed the rationale for building a custom, dual-chamber integrated device, noting several issues with trying to find a workable off-the-shelf pump. He noted that most current pumps are class II devices, though the Bionic Pancreas will be Class III. His remarks further highlighted that the team is not building a “pump,” but a “system,” requiring a totally unique and different user interface. He mentioned Abbott several times as a company that “pulled back” to focus on the type 2 arena with FreeStyle Libre – there was originally a plan to license the algorithm to Abbott for commercialization. Dr. Damiano concluded that building their own pump platform was actually easier than modifying current offerings. He admitted that his remarks in the past – “industrial collaborators” – have been deliberately cagey, since this has been in the works for some time.
• “We have built the first dual chamber pump over the past 18 months. We’re calling it the ‘iLet.’” It has been built to satisfy FDA requirements for a Class III medical device; for now, it is unclear who will manufacture the device or how it will be sold commercially.

• The touchscreen iLet device includes separate chambers for glucagon and insulin (prefilled is the goal), Dexcom integration, and a built-in control algorithm. The current version is still very much a prototype – it was literally shipped straight to Orlando – and the plan is to improve the device’s touchscreen and size over the next nine months. It’s currently the surface area of an iPhone 6 and about 2.5 times as thick, though the hope is to reduce it down to an iPhone 3 in screen size and make it much thinner. Right now, it’s a resistive touchscreen, which requires fairly hard presses to navigate through the menus. The plan is to switch to a capacitive touchscreen before a clinical trial takes place next year. Overall, the current prototype device is much smaller than the research platform used in outpatient studies to date (iPhone/Dexcom G4 brick), though bigger than current pumps on the market.

• The team hopes to switch to a capacitive touchscreen e-ink display, similar to those on the Amazon Kindle. This will enable a much thinner device that uses less power and offers a better user experience. The iLet prototype is currently powered with AAA batteries; we assume the screen change could enable a change on this front too.
• The team is building a custom, dual lumen infusion set for insulin and glucagon. These come out of separate chambers of the pump, but merge and run together like speaker wire. The plan is modular design, which will enable swapping out the glucagon or insulin lines independently – very smart. In the past, Dr. Damiano has talked about a snakebite dual cannula, meaning one patch on the body.
• The iLet system will also include a separate Bluetooth-enabled meter that will wirelessly send values for CGM calibration. These will avoid errors from manual entry. The FDA will approve the BGM as part of the Bionic Pancreas system. In a follow-up conversation, Dr. Damiano said this was a Boston-based company; we’re not sure who.
• Dr. Damiano intends to have Bluetooth connection from the iLet to a nearby smartphone, enabling cloud services. We’d note that the pivotal trial will not use remote monitoring. The tradeoff of adding a cellular chip to the iLet, of course, is the battery life, size, and cost. The idea of leveraging a nearby smartphone for cloud connectivity arguably offers the best of both worlds.
• Notably, the Tidepool team help build the user interface, which Dr. Damiano called “gorgeous.” We agree that it’s pretty user friendly for a device that is infusing two drugs through a complicated algorithm. It has retained the qualitative meal bolusing that has been a hallmark of the Bionic Pancreas. Several screenshots are included below.
  
  • Home screen: Shows the current CGM value, insulin, and glucagon dosing. Meal boluses are illustrated with circles (larger announcements get bigger circles). See above.
  • Lock screen: The vision is for a smartphone like design, with one button to wake the device up, but otherwise a touchscreen interface. The lock screen shows icons with the system status and a unique shape-based unlock sequence (touch the circle and then the square).

• The status screen: Offers a very quick look at how many days the CGM has been running, how long the infusion sets have been running, and more.
• Meal announcement: The main interactive component. The system has retained the qualitative dosing strategy of typical, more than typical, less than typical, in line with Dr. Damiano’s goal of “Diabetes without numbers.” A screen also asks what time of day the bolus is taking place, we assume allowing for greater adaptivity. We’re very happy that patients will have the opportunity to announce meals – it might be easier for some not to do this but in the first gen, having the chance for this we think will actually make some patients (similar to an exercise button) feel more in control.
• A pull down menu offers the ability for a glucagon burst (G-Burst – super cool name), changing the target, and manually entering a blood glucose for calibration (in case the Bluetooth-connected meter is unavailable).  
• The team openly admits that the iLet is still very much prototype, but they seemed very enthusiastic about this early version. It was shipped direct to Orlando – tight timing indeed! There seems to be a clear pathway to improving the size and form factor over the next nine months, and we look forward to seeing how that progresses. The hard part, of course, is drawing a line in the sand between further hardware improvements and getting something to market fast.    
  
  • “The goal is to build a device that makes diabetes management disappear. Then we will worry about the device disappearing.” Dr. Damiano said they have not forgotten about a Bionic Pancreas patch pump version, which is alongside many other ideas about how to improve the device’s size, weight, and form factor. The bigger goal is to get something done quickly and on the market. Said Dr. Damiano, “As it is right now, most of you would queue up to get one of these things” – this remark was greeted by enthusiastic nods from the audience.
• In discussing the two-phase, 6-12 month pivotal study, Dr. Damiano called Xeris’ glucagon the rate limiting-step in the Bionic Pancreas timeline. The team will conduct a four-site bridging study in Q2-Q3 2016 with the iLet, Dexcom Gen 5, and Xeris’ stabilized glucagon. This would test the device in a short, several week experiment. If that goes well, the hope is to begin a pivotal trial in January 2017.

• Dr. Damiano expressed significant confidence in the FDA roadmap, suggesting both the drug and device divisions have signed off on the pivotal study plan (“completely understood now”). We last heard about this trial at ADA and have reviewed the design below. Dr. Damiano emphasized the parallel group design, something the team has not done before (they’ve done crossover designs in the past).
  
  • The 480-person Bionic Pancreas pivotal trial will randomize patients to either the bionic pancreas (n=320) or usual care (n=160; MDI or CSII monitored with blinded CGM) for six months. At the end of six-month bionic pancreas phase, 107 patients (1/3) will remain on the system for six more months to gather chronic glucagon exposure data (at the FDA drug division’s request). The 160 usual care participants will then go on the bionic pancreas for three months (an “incentive” study – brilliant! Though it’s not as if patients don’t have an incentive to try to get into the trial, this is an incredible incentive to stay in the trial), offering all pivotal study participants a chance to use the system. The co-primary endpoints are A1c at the end of each arm and % time <60 mg/dl for the last three months of each arm. This seems brilliant since payers are particularly interested in hypoglycemia and presumably so is the FDA. Notably, the study has no remote monitoring. We were curious about overall “time in zone” and assume that could be a secondary endpoint. “Time in hyperglycemia” can of course depend heavily on how disciplined patients are on eating.
  • The multi-center study is slated to take place at 16 sites across the United States, with some very big name principal investigators: Jaeb (Roy Beck), MGH (Steve Russell), Joslin (Howard Wolpert), Stanford (Bruce Buckingham), University of Washington (Irl Hirsch), UCSD (Robert Henry), Henry Ford (Davida Kruger), Barbara Davis Center (David Maahs), CHOC (Mark Daniels), UT Southwestern (Perrin White), UT San Antonio (Daniel Hale), Nemours (Nelly Mauras), Emory (Andrew Muir), Ochsner Clinic Foundation (Lawrence Blonde), Cleveland Clinic, Naomi Berrie (Robin Goland).
  • A PMA submission is expected to occur after the last subject completes the bionic pancreas arm at ~ nine months after the start of the first subject (~4Q17). This will happen while the chronic glucagon part of the study (from month six to month 12 in the bionic pancreas arm) is still ongoing – a testament to the FDA’s eagerness to get this review done quickly, according to Dr. Damiano.
  • The pivotal study will cost an estimated ~$14 million, and the team has received “a fundable score” for the major NIH artificial pancreas UC4 grant. Dr. Damiano acknowledged “it’s not in the bag,” but hopefully high enough to get some funding for the trial. As we understand it, the recipients should be notified soon; groups like Cambridge and UVA are also looking to this to fund large-scale efficacy trials of their insulin-only systems.
• “We need you guys to step up and help. Let’s get out and raise some money and get this done.” The team needs ~$3.5 million in the next 12 months and ~$4.5 million to fund things through the pivotal stud (18 months away). One attendee suggested starting a Kickstarter campaign to raise money. The Bionic Pancreas team has done an impressive job crowdfunding – the Go Bionic challenge (launched at FFL last year) raised an impressive $1.2 million as of last December. Notably, the team has already received four $5,000 checks in the past two days. Although this funding is obviously serious funding that is challenging to raise, it is nothing like the amounts needed to fund drug trials (that often have costly required CVOTs).
• Now that the pivotal trial design is locked down with the FDA, discussions will begin with CMS and payers like Kaiser. Dr. Damiano wants to put the study design in front of CMS and see if the payer is comfortable with the primary and secondary outcomes. “We don’t want to do a huge pivotal study and find out CMS wanted something else.” In the second half of this year, Dr. Damiano plans to start those reimbursement discussions; notably, the team has already begun engaging private payers like Kaiser. This is incredibly impressive proactivity from the academic (and increasingly commercial) group!

Choosing Wisely – 5 Years of Patient Surveys and Your Next Diabetes Device Decision

Richard Wood (CEO, dQ&A, San Francisco, CA) and Adam Brown (Close Concerns, San Francisco, CA)

See below for the tables Adam and Richard provided to break down the key features, drawbacks, and upcoming pipelines of the main pumps and CGMs in the US.

Animas Vibe

Insulet OmniPod

Medtronic MiniMed 530G

Tandem t:slim

*Some patients call rechargeable an advantage. We’ve heard others say it’s a hassle.

Dexcom G4 Platinum with Share

Medtronic Enlite

--by Adam Brown, Emily Regier, and Kelly Close