November 2-4, 2017; Washington, DC; Full Report – Draft

Executive Highlights

Hello from Bethesda, where our team attended the 17^th annual Diabetes Technology Meeting. Below, we’ve divided all 29 of our highlights from the conference into the following categories: (i) CGM Highlights; (ii) Automated Insulin Delivery; (iii) Smart Pens, Insulin Dose Titration, Clinical Decision Support, and BGM; and (iv) Insulin, Insulin Delivery, and Insulin Monitoring. Key coverage includes brand new Dexcom G6 results from four aggregated feasibility studies (9.3% MARD!), very strong 670G real-world CareLink data, Bigfoot AID topline feasibility results, and the first look at screenshots of the U500 Lilly Omnipod PDM. We were also pleased to congratulate Harvard’s Dr. Frank Doyle for winning DTS’ Artificial Pancreas Award, as well Sansum’s Dr. David Kerr for winning the Diabetes Technology Leadership Award. For all this and so much more, read on.

CGM Highlights

Dexcom G6 No-Cal Feasibility (N=165): 9.3% MARD vs. YSI; Decision Support Screenshots; Verily Gen 1 Updated Design; Diabetes education “Programs”; Smart Pens!

Following last year’s initial no-calibration G6 feasibility accuracy data, Dexcom’s Peter Simpson shared brand new results (9.3% MARD!) from four aggregated feasibility studies with the same platform. He also discussed forays into connected pens, AID, the Verily-partnered sensor pipeline (modified design for gen one), decision support and CGM-enabled diabetes management programs (first screenshots), smartwatch partnerships (finally a mention of direct-to-Apple-Watch transmission). With Abbott’s factory-calibrated FreeStyle Libre sensor coming to the US market by end of year, the pressure is on Dexcom to eliminate fingersticks – fortunately, the company shared on its 3Q17 call that G6 was submitted to FDA with one fingerstick calibration per day in 3Q17, but there is also now a pathway to launch “no calibration” G6 sometime before the end of 2018. Highlights and screenshots below!

• Accuracy for the next generation Dexcom CGM without calibrations from four aggregated feasibility studies (n=165 adults + pediatrics) was highly impressive and in line with DTM 2016 data: an MARD of 9.3% vs. YSI at five in-clinic visits (n=4,555 paired points) – with no calibrations. Outliers were uncommon, with a remarkable 91% of readings within 20%/20 mg/dl. Even on day one, MARD came in at 10%, with 89% of points within 20%/20 mg/dl – this is certainly strong enough for dosing insulin. The company also broke out impressive data on accuracy in hypoglycemia (conferred by a membrane that blocks out background signal): a mean absolute different (MAD) of only 8 mg/dl vs. YSI and 94% of readings within 20 mg/dl. Mr. Simpson reminded the audience of the new sensor’s removal of the acetaminophen contraindication (lots of people will be happy about this). He later noted that the company is “very excited” about the product and confirmed the prospect of launching in 2018. As a reminder, G6 was filed with FDA for use with one calibration/day in 3Q17, but there is also an FDA pathway that could enable a G6 no-calibration launch in 2018, either after the one-calibration version or instead of it. (This will be determined by FDA discussion over the coming months.) The slide (see below) positioned the next gen as “no calibration,” perhaps lending more confidence that G6 will indeed launch from the get-go with no cal.
• We haven’t yet seen accuracy data from the large G6 pivotal trial testing one calibration per day (n=300+ and 30,000+ matched CGM-YSI pairs). In Q&A, Mr. Simpson shared that MARD is important, but the “next layer of goals for accuracy” right now is to eliminate outliers, noting that patients trust the system more and have less false alarms when there aren’t outliers.

• Accuracy was strikingly comparable to the recently-FDA-approved factory-calibrated, 10-day wear, 12-hour warmup Abbott FreeStyle Libre (MARD 9.7%, 91% of values within 20%/20 mg/dl; see Libre’s US label here, “Performance” section). Of course, there are meaningful product differences (real-time vs. flash, alarms vs. no alarms, form factor, cost), and Abbott may have a 6-12 months head-start on no-calibration in the US, depending on when G6 launches in 2018. Next year is going to be quite the year for CGM in the US!
• Mr. Simpson didn’t actually refer to the “next generation” sensor as G6, and neither did the slide deck. We’re not sure how deeply to read into the omission, because all other aspects of the system are equivalent (form factor, applicator, 10-day use, 2-hour warmup). It is possible that the no calibration version will be called something different, particularly in the scenario that Dexcom needs to differentiate it from the one calibration/day version.
• A comprehensive forward-looking slide showed specific decision support screenshots, implying a CGM-based bolus calculator that includes trend information. The slide also showed “CGM enabled diabetes management programs” focused on exercise, diet, sleep, and medication optimization. Great news!

• The same slide also showed a slightly flatter gen one Verily on-body profile, at least relative to what we saw at DTM 2016. We think the updated gen one will be more competitive with Abbott’s FreeStyle Libre.  This gen one will move Dexcom to a smaller wearable and a fully disposable design. Per Dexcom 3Q17, timing on the Verily gen-one product depends on the G6 no calibration regulatory strategy.

• Also in line with 3Q17, Dexcom’s slide showed a connected pen and automated insulin delivery pump partners (Tandem, Insulet, Beta Bionics). The 3Q17 update suggested there are “irons in the fire” on connected pens, but did not provide a concrete update. The picture in the slide was a generic illustrated pen, which makes it hard to know who Dexcom is working with at this stage... All three insulin players are working on smart pens – Lilly is a Companion Medical investor, Sanofi is a Common Sensing investor/partner, Novo Nordisk has its own smart pen piloting in Sweden – so we’d guess many partnerships are possible here.

• For the first time, a Dexcom slide showed the direct-to-Apple Watch, cloud-connected potential with Series 3. Notably, Dexcom has not actually commented on this since Apple announced the potential in June. We see enormous potential for this on a convenience front, especially for kids (i.e., no need for a phone to be carried around). The slide also showed the newly launching G5 touchscreen receiver and the just-signed Fitbit Ionic integration partnership (launching in 2018). Mr. Simpson stressed the priority to make the CGM experience seamless for patients. Data on the wrist without a phone nearby will be a big step forward in our view. Now, we’d just love to see the experience grow more seamless for ALL customers, namely Medicare beneficiaries who are ludicrously not allowed to share data with caregivers and providers.

• The public API platform that launched in September has >300 registered developers and seven data partners including One Drop, Tidepool, Rimidi, and Nutrino. While Apple Health data sharing is good for many iOS users, this API integration will enable an even bigger ecosystem of useful CGM data apps (e.g., Android and beyond). We’re very excited to see Dexcom pushing this ahead and hope to see far more partners and users get on board.
• Mr. Simpson made some enticing comments during Q&A on wear time and aspirations: “The biggest challenge in extended sensor wear is reliably the adhesive patch. There’s a lot of science behind that – we’re working on some custom adhesives, 90% work up to 14 days, possibly longer. Our sensors will last for months on the benchtop – in one publication, a sensor lasted for three months. The foreign body response limits it for some people. 14 days is fairly straightforward, but then you have to deal with biology past that. Membranes and manufacturing consistency comes up, as we scale to tens of millions of devices per year, that’s our focus.” We wonder if a 21-day sensor is possible with the right adhesive design, or perhaps even a 30-day design.

Medtronic’s Sugar.IQ Improves TIR by 33 Mins/Day, Good Engagement; ~10.4% MARD for GS3 in Real World; 670G Peds Trial Complete (7-13 Yrs); Now ~10,000 on 670G

Medtronic’s Dr. Robert Vigersky shared new Sugar.IQ outcomes data and reported encouraging accuracy data on the Guardian Sensor 3 (~10.4% MARD vs. fingersticks in real-world 670G use). In an email conversation with the company related to this talk, we’ve subsequently learned there are now “about 10,000” patients on the MiniMed 670G, a big increase since the last update (~1,000) and nearly one-third of the ~35,000 in the priority access program. The IBM Watson-partnered Sugar.IQ pattern recognition app showed a small benefit on time-in-range in the continued limited launch, but did show very good engagement, positive responses to the “insights,” and a decrease in prolonged hypoglycemia and hyperglycemia events >120 minutes (see below). The app is expected to launch in tandem with the Guardian Connect Mobile CGM later this year (per Medtronic 2Q17), though the latter is still under FDA review (over a year now). This app will be critical for Medtronic as a CGM differentiator, since Guardian Connect as a standalone CGM lags behind Dexcom and Abbott on other important device metrics (daily calibrations, phone/Watch device compatibility, on-body form factor). On the plus side, Guardian Sensor 3’s accuracy in both the real-world setting in adults and the now-complete pediatric (ages 7-13 years) 670G trial were confidence-inspiring – a continued MARD of ~10% (~3 calibrations per day). There was no update on the constrained sensor manufacturing due to global sensor demand and storm-related global manufacturing disruptions; we continue to assume Guardian Sensor 3 sales won’t really pick up until early next year.

• In Sugar.IQ’s continued ongoing “limited learning launch” phase, 256 users showed encouraging engagement metrics. In an n=136 subset of users (with 2+ weeks of data), Sugar.IQ’s glycemic insights helped increase time in range by a modest 33 minutes per day. Users spent an additional 2% of the day in range (baseline not given, not statistically significant), as well as 14% fewer lows longer than 120 minutes per year (p<0.001) and 3.9% fewer highs longer than 120 minutes per year (p<0.001) – the latter were very strange metrics, and we’d speculate it the more traditional time <70 mg/dl and >180 mg/dl were not significantly changed (given the small bump in overall time-in-range). Of course, reductions in prolonged events more than two hours are very positive and presumably of strong interest to payers. Within a week after a low glucose “insight,” 55% of users had fewer lows, with an overall 2.4% less time spent below target; within a week after a high glucose insight, 54% of users had fewer highs, with an overall 1.7% less time spent above target – we assume the latter were absolute reductions, meaning ~30-minute daily improvements in time spent low/high after insights. These are fairly modest, but presumably the group on the app is doing quite well at baseline. On average, participants in the study used the app 2.1 times per day – indicating it is engaging and could drive good ROI from the pattern recognition. Users “liked” 86% of the nearly 4,700 insights generated in the period, and 68% were logging food (2.8 items/day, on average). This analysis was part of the limited learning launch, from which we saw preliminary data at ADA (smaller n of 81). FDA review of the Guardian Connect Mobile CGM system remains the gating factor for launch. As a reminder, Sugar.IQ has been very delayed from the initial guidance to launch before the end of 2016.
  
  • Dr. Vigersky emphasized that “simple, judgement-free nudges can lead to sustained behavior improvement.” Aka…“your Jewish mother in an app.” We think Sugar.IQ has done some nice things to pull more insight out of CGM data, particularly the app’s “motivational” insights. How much value will it add to Guardian Connect? Will a non-early adopter population use the app? Will it emerge as a revenue source for Medtronic over time?

• Dr. Vigersky highlighted data from the first ~3,000 people on the 670G (see Dr. Sherr’s talk for more detail), and we’ve since learned that “about 10,000” people are now on the MiniMed 670G (a 10-fold improvement since the last update at Keystone). After Hurricane Maria hit, Medtronic conveyed via an email that patients in the 630G to 670G Priority Access Program can expect to receive pumps and transmitters in the second half of November, with Guardian 3 sensors to follow “soon” after, based on patients’ sensor re-order date. As of the August financial update, there were close to 35,000 patients enrolled in the Priority Access Program, meaning close to one-third have a system at this point. Considering FDA approval came ~13 months ago, it’s surprising how long this product has taken to trickle out. Of course, Medtronic is also the first to launch hybrid closed loop, so the caution is understandable. Medtronic has also historically not been a “CGM” company, but is now required to climb the learning curve and really scale up manufacturing quickly. Per the October email update, new 630G/670G pumps were expected to ship by the end of October, with sensor and transmitter orders expected to ship by the end of 2017/early 2018.
• Guardian Sensor 3 accuracy has remained remarkably consistent through all phases of 670G deployment, with a MARD between 10.3% and 10.6%. The figure below shows the progression – from 10.55% MARD vs. YSI in the pivotal trial (3 calibrations/day), 10.3% MARD vs. SMBG in the continued access phase, 10.4% MARD vs. SMBG in the customer training phase, and 10.4% MARD vs. SMBG in the formal launch (the latter three are on ~3.2 calibrations/day). Dr. Vigersky called the data “very reassuring,” to know that performance in the real-world matches that seen in the clinical trial. The real Achilles heel of Guardian Sensor 3 is the calibration burden (3-4 recommended per day), which will be critical for Medtronic to manage as patients compare to Abbott’s no-calibration FreeStyle Libre and Dexcom’s upcoming G6 (no-cal or 1 cal/day). We wonder what the hold-up is at FDA for Guardian Sensor 3 – is it about human factors, manufacturing, a non-adjunctive claim, or something else?

• Over on the pediatric side (data from the 7-13 year old 670G study), the Guardian Sensor actually performed with a slightly lower MARD of 9.9% on two calibrations per day (999 paired points). Nice! Further, 89.5% of points fell within 20%/20 mg/dl, very strong data for Medtronic. We look forward to seeing the glycemic outcomes from this study – Dr. Vigersky previously indicated in April that the data would be submitted to FDA by the end of the year. We’ll hope to hear on update on Medtronic’s upcoming 3Q17 call.

• Patient-reported outcomes on the Guardian Sensor 3 are quite positive. In a survey of 2,231 670G users: (i) 92% trust the system to help manage their glucose levels; (ii) 76% are extremely or very satisfied with MiniMed 670G; and (iii) 75% are extremely or very satisfied with Guardian Sensor 3. As Medtronic speakers keep pushing, this news sensor line really is something of a new dawn and a door-opener for the company. Anecdotally, we’ve heard this too, including from former Dexcom users – the new Medtronic sensor really delivers relative to prior versions. Near-term, Medtronic just has to scale manufacturing! There are more than enough patients for multiple companies to convert …

Real-World Libre Data (>235k Readers; 2.3B glucose Readings): Scan frequency Tied to Reduced A1c & Hypo

Marking the first major US conference in which Abbott’s FreeStyle Libre (real time) could be discussed as an FDA-approved product, Dr. Tim Dunn presented new real-world data collected from September 2014-2017 (n= 237,747 readers) demonstrating strong correlations between the number of daily scans and reductions in estimated A1c and time spent in hypoglycemia (<55 mg/dl; see below). With over 237,000 readers as of September, this data set is now more than quadruple the size relative to the first glimpse in February (55,000+ readers). Notably, the curve of scan frequency vs. eA1c looked pretty much the same. Dr. Dunn also showed data recently presented at EASD supporting an inverse relationship between number of scans and time spent in hyperglycemia (>180 mg/dl), as well as interesting regional comparisons between Germany and France (see below). For time spent in hyperglycemia, the two countries exhibited minor differences: in Germany, time spent in hyperglycemia dropped by nearly 4 hours/day from a baseline of 9.9 hours/day, while in France, time spent in hyperglycemia decreased by 3.6 hours/day from a high baseline of 10.5 hours/day – either way, more scans drive less hyperglycemia. However, for time spent in hypoglycemia, time dropped 9.3 minutes/day from a low baseline of 35.9 minutes/day in Germany, while in France, time decreased by 18.6 minutes/day from a much higher baseline of 59.1 minutes/day – notably, the benefits from scanning appear to level off at <20 scans/day, which makes sense (that would be more than once per waking hour). We wonder what cultural, healthcare, or other factors could underlie these differences – this data set seems like a treasure trove and only the surface is being scratched right now. Future directions for these real-world studies include generating observations over time, observing populations with recent approvals or reimbursement (possibly Belgium or France), or most intriguingly, trying to identify strategies of Libre usage (around hypoglycemia, pre/post-meal, insulin dosing, and exercise) that beget glycemic success.

• Dr. Dunn did not comment on the impending US launch, which is expected in retail pharmacies by the end of the year. Read more in out Abbott 3Q17 report.

• Dr. Dunn showed accuracy data for the 10-day, 12-hour warmup US version of FreeStyle Libre (based on 5,772 paired CGM-YSI points): MARD was 9.7%, and 91% of values came within 20%/20 mg/dl. More stringently, 82% of values were within 15%/15 mg/dl. No data were presented in hypoglycemia, though we’ve discovered the label is now posted here on FDA’s website (key performance data below) – FreeStyle Libre reports a strong 81% of points within 20 mg/dl for glucose levels 51-80 mg/dl, and 58% of points for levels 40-50 mg/dl. Unlike the Pro version, the real-time US version of FreeStyle Libre (with the longer 12-hour warmup and shorter wear time) does not have a contraindication for hypoglycemia. Read the full performance data here.

• FreeStyle Libre, which obtained FDA approval in September, is now available in 42 countries, with full or partial reimbursement in 19 of them. Here is a non-exhaustive list of markets with coverage – non-exhaustive because there have been two additions since Abbott last shared specifics! The clip at which countries are deciding to reimburse the sensor is impressive, and presumably stems from the two RCTs (in type 1 and type 2), the growing real-world data, and the appealing price point relative to fingersticks and traditional CGM.
• During the panel discussion, Dr. Dunn mentioned that he was surprised by the high number of daily scans apparent in the real-world data – 16 times/day on average. This is indeed quite notable, considering this is nearly half of FreeStyle Libre global installed base (assuming 1 reader = 1 person, and there are now 400,000 users). As Dr. John Pickup noted, some individuals averaged 40-50 scans/day, raising the question of the psychosocial impact of CGM. Might CGM actually make some people more anxious or obsessed? Psychosocial expert Prof. Katharine Barnard stepped up to the mic to reassure that people appreciate the reassurance associated with CGM and that published data exists demonstrating specific quality of life benefits due to CGM. As she pointed out, scanning 40-50 times/day might be no different than the high frequency at which we check our phones (or may be less for some). Dr. Dunn cited Abbott’s type 1 study published in The Lancet showing improvement in quality of life associated with the Libre, but acknowledged that it is an area requiring further investigation. We suspect scan frequency will change depending on the population (early adopters vs. late majority), and the benefit of no fingersticks will be a huge quality of life driver for everyone.

Reimbursement for interpretation of CGM Data May Decline Slightly in 2018 – New Fee Schedule Proposes $36.72 for Code 95251

In a talk on CGM reimbursement, Dr. Allan Glass (The Endocrine Society) said that the reimbursement rate for physician interpretation of CGM data with report (95251) may decline in 2018 – and it’s already a low $44.50 through Medicare! Since the talk on Thursday, the new fee schedule has actually come out, and reimbursement for this code has indeed declined 17% to $36.72. We are extremely frustrated to hear this, since stronger reimbursement for CGM data interpretation could encourage more sensor prescribing and HCP engagement with the results. Until the AMA prints the final fee schedule, who can bill, and the limits (i.e., how many times an HCP can use a code within a time frame), it will not be final. More details are expected in the coming months, probably closer to January 2018. There are important nuances to this – e.g., when and where codes can be used – and we seriously hope the final AMA publication at least broadens the criteria of who can submit this for reimbursement. Interestingly, this reduction is based on time/motion surveys of physicians, which could mean they are getting faster at reviewing CGM data with the next-gen reports that are now available (Abbott’s Libre View, Dexcom Clarity, Medtronic CareLink). On the other hand, we hope it does not further dissuade providers to use these codes – e.g., will they bother, given the low reimbursement? If physicians are monitoring hundreds of patients remotely, could they bill each month for each patient? On a positive note, existing code 95250 for HCP-owned professional CGM (sensor placement/hookup/training) is proposed at $156.58, almost identical to the current $159.70. We’re concerned about the poor reimbursement providers continue to receive for CGM. Will this improve? Medicare definitely deserves kudos for finally reimbursing Dexcom’s G5 CGM in type 1/2 insulin users, but payment reform needs to make CGM prescribing/utilization sustainable for providers too. 

• A new code, 95249, now exists to reimburse physicians for patient education and setup of personal real-time CGM (i.e., used by private payers for all CGMs; currently only Dexcom’s G5 under Medicare). The proposed amount (that came out Thursday night) is $56.15 as a national average – low, but obviously better than nothing. This can only take place if the patient comes into the office (i.e., no telehealth), and it can only be reported once during the entire time someone owns a CGM (i.e., no reimbursement for retraining or refreshers).
• We also learned that CMS’ reimbursement rate for Dexcom’s G5 (~$250 per month for supplies, ~$250 per receiver) is actually based on the home glucose monitoring that CGM replaces, not on the cost of the actual CGM device itself! This did not at first glance make sense since BGM reimbursement is much lower. According to Dr. Glass, this may mean future CGMs covered by Medicare will get the same pricing (though obviously things can change). This could be a positive for the field if longer wear time or lower cost systems (e.g., Abbott’s FreeStyle Libre, Dexcom G6/Verily products) are reimbursed at the same rate. Of course, it would be even better if Medicare understood that SMBG is not equivalent to CGM.

Senseonics Aiming for Gen 2 Sensor that Lasts One Year & “Relies Less on User Interaction, Such as Calibration”

Senseonics is hard at work developing a second-gen sensor, “looking for use up to a year” and “relying less on user interaction, such as calibration,” according to R&D Director Dr. Andrew DeHennis. He optimistically pointed out that there is just one factor limiting the extension of duration past the recently CE-marked 180-day indication – signal degradation of the indicator that cleaves boronic acid groups via reactive oxygen species – but the team is working on mitigation solutions. If Senseonics were to succeed in developing a 365-day sensor, requiring just one clinic visit per year, its sensor would last nearly 26-times longer than the next competitor in the EU (Abbott’s 14-day FreeStyle Libre), and 36-times longer than that FreeStyle Libre in the US (as of now). Of course, this was also significantly enhance the value proposition of Senseonics’ implantable CGM, which still does require a small on-body transmitter. On the other gen two proposition of eliminating fingersticks, we were glad to hear this project is still high on the list of priorities; we haven’t heard about it in a couple quarters. Last we heard in May, this sensor was in human feasibility trials. The sensor is expected to use redundant glucose-sensing capabilities, facilitating improved accuracy, longevity, and functionality. The original 90-day Eversense with the first-gen on-body transmitter is currently under FDA review, with an Ad Comm expected in 1Q18. It is currently available in 12 EU countries and South Africa. Read more in our Senseonics 3Q17 report.

OSU’s Academic Work on Contact Lenses to Measure Glucose – Early Stage, But Promising Use of Display Industry Technology

Dr. Greg Herman presented early-stage work on Oregon State University’s efforts on contact lenses to measure glucose. He immediately clarified that the team’s approach is different from Verily/Novartis, who are using a more typical amperometric (electrochemical) sensor with a copper antenna (and on which there has not been an update in over a year; the original ~5-year time frame for launch (~2019) is quickly approaching!). Notably, Dr. Herman’s team is leveraging core technology from the display industry, which enables up to 3,000 sensors per square millimeter – this allows for incredibly low costs and highly automated, large-scale manufacturing. OSU’s approach uses flexible transparent, “amorphous indium gallium zinc oxide (IGZO) field effect transistors.” Glucose oxidase is immobilized on IGZO – read how it works to measure glucose (via a chemical reaction and pH changes) in the bullet below. Notably, measurements of other analytes and environmental conditions are also possible with this technology. The sensor does not have acetaminophen and ascorbic acid interference, and can reportedly measure down to much less than the tiny concentrations of glucose found in tears. The sensors are fully transparent – an advantage for contact lenses – and the flexibility allows for application to other surfaces, including catheters. (Presumably this makes a combined CGM/insulin infusion set possible.) Two big questions, of course, are whether (i) tear glucose can be reliably and accurately measured; and (ii) correlates strongly with blood glucose. Dr. Herman noted concentration as a challenge: tear glucose levels are ~10x lower than blood glucose concentrations, meaning any sensor needs to be quite accurate. In one recent publication in people without diabetes (n=10), the correlation between tear and blood glucose was notably high (r²= 0.96) – of course, doing so in an ambulatory setting in people with diabetes will be important. The OSU contact lens work is still early, and audience questions highlighted many nuances that will be key to address – e.g., what about temperature, stress, environmental conditions, changes in tears, etc.? The use of consumer electronics manufacturing seems quite promising as a general approach to drive sensor costs down. Near-term, we’ll be fascinated to see if Verily/Novartis’ efforts come to fruition.

• How does it work? Glucose oxidase is immobilized on IGZO using self-assembled monolayers, which have aminosilane groups and glutaraldehyde. Gluconic acid is formed through the biocatalytic oxidation of glucose by glucose oxidase, and this locally decreases the pH near the IGZO surface. This results in positively charged aminosilane groups, which are electron acceptors located at the IGZO surface. Electrons tunnel into these acceptors and reduce the conductivity of the IGZO film. The change in the IGZO conductivity can be directly correlated with glucose concentrations.
• “With most technology, there are going to be struggles. There needs to be a lot more work on how environmental conditions affect glucose concentrations (in the eyes). One of the nice things with this technology is we can incorporate other sensing technologies and measure a range of analytes. We can measure temperature and concentrations of other biomarkers. There are going to be potentially 10-100 different sensors that we can be integrating. With AI, we can start correlating that information. If you only had one sensor monitoring glucose in the eye, that would be difficult with all the environmental and physiological factors.”  

• Glucose monitoring contact lens publications from Dr. Herman’s lab: A field effect glucose sensor with a nanostructured amorphous In–Ga–Zn–O network (Nanoscale 2016); Glucose Sensing Using Functionalized Amorphous In-Ga-Zn-O Field-Effect Transistors (ACS Appl Mater Interfaces 2016); Fabrication of a Flexible Amperometric Glucose Sensor Using Additive Processes (ECS J Solid State Sci Technol 2015)
• Funding for the contact lens research came through the NIH, the Helmsley Charitable Trust, JDRF, and ONAMI – see the website here.

Pacific Diabetes All-In-One CGM/Infusion Set to Enter Feasibility Study (N=10); Looking for Commercial Partners “Soon”

Dr. Robert Cargill shared that Pacific Diabetes Technologies’ (PDT) all-in-one CGM/infusion set is progressing nicely, with the sensor showing promising results in swine and the first generation combo device scheduled to take part in a feasibility artificial pancreas study at OHSU “within the next six months or so.” The first-generation design, which is in the “later stages” of IDE submission prep, is comprised of a flexible sensor surrounding a rigid cannula with a laminated 25-gauge needle (“a little large, but what we thought we could get into trials quickly”). Dr. Cargill expects to conduct an eight-hour in-patient feasibility study (n=10 T1 adults) in the next six months, driven by OHSU AP system and with Pacific Diabetes’ first-generation device participating as a “bystander” – presumably meaning it will not feed into the algorithm and results will be compared to a standard commercial CGM. Dr. Cargill’s team is currently focused on designing the second-generation product, which is basically turned inside-out from gen-1 – the cannula is embedded inside the sensor so that the fluid path runs down the center of a thermoplastic core. The result is a much more flexible device. The development team is working on accelerating the warmup period, as well as improving the stability and lifetime of the sensing enzyme, aiming for at least seven days. Infusion set lifetime is obviously a concern as well – Dr. Cargill shared that an infusion set with redundant ports (“sprinkler” design) is currently in development to address this issue, and he is also closely following Capillary Biomedical’s work in the area. Now, the group is moving towards developing the entire CGM-infusion set and will begin looking for commercial partners to help scale manufacturing “soon.” We like the vision of an all-in-one CGM/insulin infusion set for pumpers, though sensors are already at 10-14 days, continue to get smaller, and continue to push into MDI – can Pacific Diabetes keep pushing ahead? Would an infusion set player (e.g., Unomedical, BD) or a CGM company (Abbott, Dexcom, Medtronic) consider a partnership?

• One of the first challenges Pacific faced was designing a sensor unbiased by the presence of insulin. When exposed to insulin, conventional, platinum-based sensors exhibit a rapid spike resembling hyperglycemia followed by eventual poisoning and loss of sensitivity. By turning to redox-mediated chemistry, Pacific Diabetes developed a sensor capable of functioning normally, showing no inappropriate glucose spike when studied in swine.

FDA’s Dr. Courtney Lias: Interoperability Will Drive Innovation (Working With HCT, JDRF) + 5 Trends in CGM, Including Factory Cal

FDA’s insightful Dr. Courtney Lias provided an excellent update on five key trends in CGM and shared continued enthusiasm for interoperability. On the latter, she noted that “interoperability can promote innovation,” get patients products faster, speed regulatory reviews, and enable more choice. FDA is working on “smart solutions” for seamless device interoperability (“low hanging fruit”), and discussions are ongoing with stakeholders – including JDRF and the Helmsley Charitable Trust! Dr. Lias said FDA will “hopefully be announcing some public opportunities for discussions on that front. We’re trying to remove barriers that don’t actually help.” This is outstanding news and we hope it drives to actionable device communication standards that companies follow – the potential here is very big, as noted in our coverage on JDRF’s new open protocol initiative for automated insulin delivery. Dr. Lias also gave a nice update on five trends in CGM, highlighting better accuracy, fingerstick replacement claims, no calibration, implantable, and better use of data/integration. Read more on these below, followed by some of our favorite slides.

• Dr. Lias specifically mentioned the past year’s approvals of Abbott’s factory calibrated FreeStyle Libre (September) and Dexcom G5’s non-adjunctive claim (December 2016) to replace fingersticks, noting FDA is “very comfortable they will be beneficial.” However, both companies will be doing post-approval studies to ensure the fingerstick replacement claims are safe. We knew about Dexcom’s study, but this is first we’ve heard Abbott also has to do one. (As a reminder, T1D Exchange’s REPLACE-BG study showed non-adjunctive use of G4 is safe.)
• Dr. Lias was quite positive on factory calibration – this is a “movement in all sensors…Calibrations can provide greater continued accuracy; however, they also are a big source of error. Many people don’t do calibrations properly. Factory calibrated sensors, as long as companies are creating stable sensors with good performance, have potential to vastly improve patients’ quality of life.” Of course, this comment is not surprising after the FDA approval of FreeStyle Libre – which was not a given! This comment bodes very well for Dexcom’s no-calibration plan for G6, which has potential to launch by the end of 2018, per yesterday’s 3Q17 update. It also bodes well for Bigfoot’s plans to use factory calibrated FreeStyle Libre in its automated insulin delivery system (pivotal in 2018, potential launch in 2020).
• Regarding “Big Data” and integration, Dr. Lias gave several valuable examples of possible CGM-driven software/apps/decision support. “You have all this CGM data; what do you do with it? How do you use mobile platforms to optimize life with diabetes, share across devices, and give data to HCPs?” Examples:
  
  • “CGM-based dosing calculators” (we assume this means meal/correction bolus advice based on trend arrows, carbs, and perhaps historical trends).
  • Clinical decision support (we assume using CGM data to help HCPs titrate therapy)
  • Mobile apps for coaching/lifestyle (e.g., last time you ate this meal, you needed this much insulin; you should take X units this time)
  • Mobile apps for integrated and personalized tracking
  • CGMs for type 2 diabetes (“a real trend,” noted Dr. Lias)
  • Automated Insulin Dosing Systems (presumably both pump and injection-based systems that use CGM data to direct dosing– either in real-time or a few times per day for injectors)
• Regarding the above, Dr. Lias believes “these are going to be coming along quickly, and in various formats.” She admitted these can be hard to assess on the algorithm front, since all the algorithms are different from each other and there is no history like we now have in traditional automated insulin delivery. Still, her comments signaled (to us) enthusiasm for the potential of CGM data + software algorithms to drive smarter and safer dosing.
• Despite improved CGM accuracy/reliability, Dr. Lias believes the field has not hit a plateau. To this end, the FDA is really working with companies on CGM manufacturing standards to improve the reliability and accuracy of products. “How is the company assuring that when they release product, it performs the way it should? That’s harder than it seems.” Manufacturing is indeed the name of the game in CGM these days, as it drives product performance and cost – two major drivers of uptake. Abbott and Dexcom have both invested significantly on this front, and Medtronic is now playing catchup.
• On implantable, Dr. Lias did not mention Senseonics’ Eversense by name (currently under FDA review). However, she said “commercially feasible [implantable] products are being manufactured. We will see whether or not they reach the market in the next several years. We will see what develops.” She noted that the on-body footprint of implantable devices is often not much different relative to current generations, an area of opportunity. As a reminder, Senseonics’ Eversense remains under FDA review, with a possible FDA advisory committee expected in 1Q18. The product currently under review is the first-gen transmitter, which is indeed quite bulky compared to the 55% thinner transmitter that has already launched in Europe.

Treatment of Type 2s “Can Be Revolutionized” with CGM; “AGP is the Holter Monitor for Dysglycemia” – Dr. Eugene Wright

Duke’s Dr. Eugene Wright Jr. beautifully asserted that treatment of type 2s “can be revolutionized with CGM.” His persuasive talk shared clinical experience using Abbott’s FreeStyle Libre Pro, though he never mentioned the device by name. (The AGP reports in his slides were obviously from Pro.) Dr. Wright argued that professional CGM provides excellent insights for HCPs and people with type 2, including those on orals – identifying hypoglycemia and 24-hour glycemic profiles, making glucose-lowering therapy adjustments, initiating treatment changes, and as a behavior modification/conversation tool. He showed multiple reports of patients with A1c values of ~7%, which masked significant highs and lows that were only identified with AGP: “A hemoglobin A1c of 7% is not a hemoglobin A1c of 7%.” Hear, hear! Dr. Wright concluded that “AGP is the Holter monitor for dysglycemia,” a great way of putting the vision. His clinical cases showed clear value of CGM in type 2, though he did not address a big question for the field: patient selection for real time vs. professional CGM. Adam posed this question in Q&A, to which Dr. Wright was honest – he has only had experience with FreeStyle Libre Pro so far. “Your point is a very good one. Should everybody be able to see all their data all the time? In patients who are on sulfonylureas or insulin, I think it’s a good idea that they get to see it. Those on other agents that may or may not cause low blood sugars, it may be less important. Periodic and episodic monitoring, along with A1c, can be useful, and probably more cost effective.” We are huge fans of 24/7 CGM use – the real-time learning and feedback is unparalleled – though wonder how the type 2 market will segment out. Will some patients get just as much value out of professional CGM at key junctures, paired with HCP advice? Perhaps this is a study worth running…

Dr. Fleming: Day of Reckoning Coming for CDER (With Respect to Acceptance of Non-Severe Hypo)

In reference to FDA’s (CDER’s) resistance to acceptance of non-severe hypoglycemia as a key regulatory endpoint, Kinexum’s Dr. Zan Fleming exclaimed “we need to get over this hurdle, and I think the day of reckoning is coming for [CDER’s Division of Endocrine and Metabolic Products]. The Division has been out of step, and has not accepted technology that has evolved to the point of regulatory quality for supporting therapeutic development.” We just learned yesterday that the EMA has approved a label update for Tresiba to reflect reduced risk for severe hypoglycemia vs. Lantus based on the DEVOTE trial, and Dr. Fleming doesn’t see how FDA will be able to resist this time in granting its first hypoglycemia claim on a drug label. Of course, this doesn’t answer the question of non-severe hypo yet, but it is a definitive positive step, as was the involvement of CDER’s Director Dr. Janet Woodcock at July’s Glycemic Outcomes Beyond A1c.

• Dr. Fleming’s Kinexum colleague, Dr. Douglas Muchmore, preceded his talk with a brief history of hypoglycemia definitions before proposing that 70 mg/dl stand as an appropriate alert level and 54 mg/dl be designated clinically meaningful and relevant for hypoglycemia and for use as a cutoff in clinical trials and for regulatory considerations. These are the bins that were agreed upon in July and will be published in a slew of upcoming papers. Dr. Fleming went further, suggesting that there is no need or practical way to prospectively validate CGM endpoints by showing the relationship between consensus-based CGM endpoints and long-term clinical outcomes. “It’d be a pretty big project, and I don’t see how you do it.” It would be more feasible, he added, to choose hypoglycemia endpoints on the basis of abundant available data and stick to them. “I believe you could hang your hat on a simple glucose level, which is justified by a large body of evidence, as a start for a reasonable regulatory approach.” Dr. Muchmore chimed in, citing evidence that counter-regulatory hormones kick in at 70 mg/dl, and cognitive impairment can set in at around 54 mg/dl. (Dr. Stephanie Amiel presented very convincing data on 54 mg/dl at EASD.) In a study of diabetic coma, of the patients involved, all had a blood glucose lower than 50 mg/dl at the time of the coma, save for one. To Dr. Muchmore, this is all the evidence that is needed – a blood glucose of <50 mg/dl doesn’t guarantee a coma, but the data is telling and does not necessitate a clinical trial. We agree! UVA’s Dr. Marc Breton commented that occurrence and depth of moderate/mild hypoglycemia also increases in days leading up to a severe hypoglycemia event.
• Dr. Fleming suggested that we actually have to be arbitrary in selecting thresholds: “Look at how we assess probability. We picked p=0.05, but why not 0.06? Why did we settle on 5% weight loss as meaningful? That’s the magic line. You want to know why? We made it up, pulled it out of you-know-where. Folks, we have to just hang our hats on what are to some extent arbitrary numbers.” Another defense of choosing glucose cut points is that the correlation between mild hypoglycemia and severe hypoglycemia is robust, and the occurrence and depth of moderate/mild hypoglycemia increases in the days leading up to a severe event. The field has done one better than pure arbitrariness, coming up with cutoffs (54 and 70 mg/dl) that are physiologically defined, and therefore likely tied to outcomes.
• Ultimately, everyone seemed to think the consensus cutoffs are viable, and tired of having the same discussion again. But we do get the feeling that the tide is turning and hope CDER hears the message – either behind the scenes, in meetings with companies, or by reading the upcoming papers. We hope the field moves to constructing a pathway to accept CGM-based data and outcomes for diabetes drugs.

Senseonics Poster Details High Real-World Usage, Strong Glycemic Data in 56 EU Patients Over 90 Days

A Senseonics poster shared real-world usage and glycemic results for 56 patients implanted with the Eversense CGM in Europe in May and followed for the 90-day sensor life. The big takeaway from the poster is that the users wore their transmitter 87.5% of the time in May (20.6 hours/day), 86.7% of the time in June (20.4 hours/day), and 86.0% of the time in July (20.2 hours/day). In the 180-day EU pivotal, median wear time was 23.5 hours per day over the first three months, and median wear time was 23.4 hours per day in the 90-day US pivotal. We’re not all that surprised by the ~three-hour decrease in real-world wear time vs. clinical trials. Wear time didn’t decrease meaningfully as the ninety days progressed (just over a 20-minute drop-off from May to June) – we wonder if this would hold true if the observation period were to stretch out another few months, and how many of the 56 opted to get re-implanted. We acknowledge that this group of patients adopted implantable CGM early and is likely therefore a highly engaged bunch, but the data is a positive for Senseonics. The poster also shared data on glucose levels: There was unfortunately no pre-sensor control data shared, but mean glucose came out to ~155 mg/dl for the 90-day period (decreasing from 159 mg/dl in May to 152 mg/dl in July). Average time-in-range (70-180 mg/dl) was ~63% (61% in May up to 64% in July). Meanwhile, time in the hypoglycemia ranges decreased from 1.6% in May to 1.2% in July for values <54 mg/dl (mean: 1.4%), and from 3.9% in May to 2.9% in July for values <70 mg/dl (mean: 3.4%).

Automated Insulin Delivery

Very Strong 670G Real-World CareLink Data (N=3,031) – TIR Up Nearly 2 Hrs/Day; <15 Year-Old Sub-Analysis Shows Nice Benefit

Yale’s Dr. Jennifer Sherr presented real-world MiniMed 670G data (n=3,031) from five months of voluntary uploads to CareLink: In the entire cohort, mean blood glucose dropped by ~8 mg/dl (baseline: 160 mg/dl) and time-in-range (71-180 mg/dl) increased by nearly two hours/day (from 65% to 73%). These real-world results show a consistent time-in-range improvement relative to the pivotal trial (when time in range went from 67% to 72%). Notably, there was not a meaningful change in hypoglycemia (low at baseline), though time in hyperglycemia came down by more than an hour per day. This is excellent news for Medtronic and provides further confidence in the three-month pivotal data. In the <15 year-old sub-analysis, on average, mean blood glucose decreased by a whopping ~17 mg/dl (baseline: 178 mg/dl) and time-in-range increased by two hours/day (from 55% to 66%). Adolescents spent 77% of the time in auto mode (18.5 hours/day), notably lower than the entire cohort’s 85% of the time in auto mode (20.4 hours/day). Of course, seeing this kind of utilization in 14-15 year-olds indicates the system is providing clear benefits, even in the tough teenage population. For the entire cohort, sensor MARD was 10.4% with 3.6 calibrations/day, though for adolescents, MARD was slightly higher at 11.8% with 3.5 calibrations/day. Last time we saw real-world CareLink data at Keystone, patients (n=730) had jumped from 63% in range in manual mode to 76% in range in auto mode – no matter which way the data is cut, early 670G users continue to see nice time-in-range benefits from this first-generation hybrid closed loop. We look forward to seeing data in even younger 7-13 year old users. As an aside, we also hope to see Medtronic move to the now-industry standard cutoffs: <70 and 70-180 mg/dl.

• Dr. Sherr also presented subgroup analyses of the three-month pivotal trial, examining outcomes just in 14-17 years-olds (n=20) and 18-21 years-0lds (n=10). Among children 14-17 years old, time-in-range increased by nearly two hours/day (baseline 14 hours), and in those 18-21 years old, time-in range increased by approximately one hour/day (baseline 16 hours) – not surprising, since 18-21 is a tougher age group, given college and transition to adult care. Increases in time-in-range were even more marked overnight, in line with the adult data. During the overnight period, insulin rates were dynamic: For the younger and older adolescents cohorts respectively, insulin was not delivered at all for 16% and 19% of the time, and insulin was delivered at a maximum rate 33% and 38% of the time. The transferal of variability from glucose to insulin is closed loop’s great promise, of course. See below for glucose tracings (grey represents the two-week run-in phase, pink represents the three-month study phase; top = overnight; bottom = 24 hours). The overnight glycemic variability for the older pediatric cohort is not as tight as would be expected – Dr. Sherr cited the smaller sample size as a possible explanation. The following day, Medtronic’s Dr. Vigersky mentioned that the 670G trial for kids ages 7-13 has wrapped up, and he has previously indicated data would be filed with FDA for a lower age indication before the end of the year.

Bigfoot MPC Algorithm Adjusts Parameters, Including Glucose Target, on Hour-to-Hour Basis; 2018 Pivotal with FreeStyle Libre

Bigfoot Director of Clinical Innovation Ms. Jen Block shared new details on the  automated insulin delivery system studied in this trial: the Bigfoot algorithm starts with a single basal rate, carb ratio, ​and ​insulin sensitivity factor, and then proceeds to adjust basal rates, carb ratios, insulin sensitivity factors, and glucose targets on an hour-to-hour basis. We weren’t aware the system was actually changing the glucose target by hour, which is quite impressive and presumably could enable tighter control at times where there is less risk of hypoglycemia (our speculation). The 48-hour feasibility trial (n=20) was displayed in the poster hall on Day #1, but Ms. Block reviewed it in more detail. The study was in 10 adults (no one over 57 years old), five children ages 7-12, and five adolescents ages 12-18. The study was designed to accommodate MDI users, a demonstration of the algorithm’s ability to quickly adjust therapy parameters in non-pumpers, and a continued signal from Bigfoot that it really wants to expand the market. The 65% time-in-range, 0.9% of time <70 mg/dl, and no hypoglycemia requiring assistance was roughly in line with other AID trials, especially since the study included (i) day one breakfast with ~30% excess insulin delivery; (ii) day two dinner with complete omission of insulin bolus; and (iii) 45 minutes of unannounced exercise. Ms. Block also hearkened back to the vClinic that Mr. Lane Desborough, Bryan Mazlish, and team developed to run over 100 million subject-days of simulation prior to the human trial. The vClinic could run the equivalent of a three-month pivotal trial (200 subjects, 100 days) in “less than a minute.” As noted in our Day #1 report, based on the extensive simulation and modeling, the team almost exactly predicted the results of the in-clinic evaluation. Ms. Block, who has many years of experience in diabetes clinical research (including lots of AID studies with Dr. Buckingham), conveyed how impressed she was by this work multiple times through the talk. Bigfoot certainly has incredible algorithmic brainpower, a cool design vision, and an exciting monthly subscription approach, though lots of execution will be needed to hit the ambitious timelines – a 2018 pivotal trial with the factory-calibrated next-gen FreeStyle Libre and a possible 2020 launch (pending FDA approval of the system, which includes a smartphone app serving as the complete user interface).

• Ms. Block displayed a timeline of Bigfoot achievements so far, showcasing the recent Timesulin acquisition, Abbott FreeStyle Libre partnership, planned 2018 pivotal trial timing, and planned 2020 commercial launch. A separate slide titled “A vision – Automated Insulin Delivery for Everyone…” (below) depicted “Bigfoot Inject” (MDI auto-titration system) and “Bigfoot Loop” (automated insulin delivery system) side-by-side, both with a Bigfoot-branded next-gen Libre, the Bigfoot app running on a phone, and pens or the Asante pump, respectively. On the former, Ms. Block pointed out how young the company is – as a matter of fact, the team will be celebrating its third birthday this week. She also indicated that the company as a whole has almost 140,000 collective days of experience living with type 1 diabetes (i.e., 384 years(!), presumably including family members of employees).

iDCL Trial Update & Summary Table: Protocols 1-4 Beginning in 2017-2018

UVA’s Dr. Stacey Anderson provided a welcome overview on the long-in-development, multi-arm iDCL trial, detailing plans to complete protocols 1-3 of the NIH-funded project in the upcoming year, as well as a future protocol 4 to test the incremental effect of adding a next-gen adaptive control algorithm from Harvard. We appreciated the clearly-laid out cadence of trials coming down the line – boy are these groups, particularly at UVA and Jaeb, going to be busy! All of the details are included in the table below – many were clarifying or new to us. In line with Tandem’s 3Q17 call, the US pivotal for the treat-to-range system (with G6 and TypeZero) is set to start in 1H18 – this has been delayed, but it seems like the hardware pieces are now worked out and we’re glad to see CGM outcomes as the key endpoints. Protocol 2 – the EU pivotal for the long-term Roche-Senseonics-TypeZero system – will require a training protocol to test the new system configuration; we’re not sure if the training protocol is set to start in 1Q18, or the main study. The language on the slide for this Roche/Senseonics system is also notable, which says “subsequent FDA presentation” –  the focus is currently on the EU market, though this is the first definitive indication that the companies are interested in US commercialization as well. Who will actually undertake the commercialization remains up in the air (as far as we know), but we’d speculate it would be Roche as the pump partner. Lastly, the fourth protocol, beginning in 4Q18 and layering on a next-gen adaptive control algorithm (Harvard Zone MPC algorithm) is exciting and presumably offers potential for tighter time-in-range. We look forward to seeing this cohort of trials progress and hopefully bring at least two commercial systems to market. As a reminder, iDCL received a remarkable ~$12.7 million in grant funding from NIH.

• Included in Dr. Anderson’s slides were images of the Eversense CGM with the inControl AP and inControl IQ embedded in the t:slim X2 pump (with a G6 CGM). See below.

• Dr. Anderson also reviewed a litany of previous studies from the UVA group, including data from home use (Diabetes Care 2016; DTT 2017), showing ~77% time in range, 1.3% time below 70 mg/dl, and 0.1% time below 50 mg/dl. She also showed closed loop studies in extreme conditions (adolescents skiing – elevation, activity, low temperature – and those with extreme hypoglycemia).

Outpatient Data on Insulet’s Omnipod Horizon: 74% TIR, 1.8% Time <70 (n=11), Mean Glucose of 150 mg/dl

Insulet’ Dr. Trang Ly shared interim outcomes from the ongoing five-day hotel study of the Omnipod Horizon Automated Glucose Control system. She summarized data from 11 patients so far, with a strong 74% time-in-range (70-180 mg/dl), 1.8% <70 mg/dl, and 25% >180 mg/dl. (As a reminder, this is the first study of the system in more free-living conditions.) Mean glucose was a solid 150 mg/dl. See the comparison below to the previous IDE trials. As she did at EASD, Dr. Ly showed the same n=1 example from a pediatric user, who entered with a mean A1c of 9.8%; on day #4, mean glucose had dropped to ~144 mg/dl, predicting an estimated A1c drop to ~6.7% (82% time-in-range). Dr. Ly did not give any launch or pivotal timing on Horizon, though an unmarked timeline slide (see below) confirmed that after this hotel study is complete, a pre-pivotal study will follow, with a pivotal as the last clinical development step. Insulet’s 3Q17 call expected a lunch of Horizon by “end of 2019” or “early 2020,” which feels quite reasonable given Insulet’s impressive pace of study progress so far – n=118 participants tested, n=7,584 hours of closed loop.

• It will be fascinating to watch Insulet and Bigfoot progress side-by-side, as both have some similarities and some key differences. Both are taking a compelling hardware approach to automated insulin delivery (i.e., their on-body components do not have a user interface, and their systems will remain in closed loop even if the PDM (Insulet) / smartphone (Bigfoot) are out of range). Both are also really prioritizing an outstanding, consumer-grade user experience. Thus far, Bigfoot has focused its pre-pivotal efforts on modeling and simulation (100 million subject-days), with only one completed clinical feasibility study to date (see highlight above). Insulet is doing more rounds of clinical testing, in addition to simulation/modeling with the UVA/Padova simulator and its own data. Both algorithms are MPC-based, though with different flavors – Insulet’s algorithm was licensed from UCSB after years of academic development (but has since had substantial changes to it), while Bigfoot’s algorithm is developed in-house and leverages machine learning (see above). We expect both to be very strong products and both to come to market around roughly the same time, assuming current launch projections are hit.

Bigfoot AID Topline Feasibility Results (N=20) – 65% TIR (70-180), 0.9% <70 mg/dl; Lane Desborough’s Remarkably Accurate Simulation Predictions

A popular Bigfoot poster gave attendees a first look at the insulin automation capabilities of the Bigfoot AID system, which has been quite stealth to date. The multi-site, single-arm safety and feasibility trial enrolled 10 children (7-18 year old) and 10 adults to wear the system for 48 hours – including meal and exercise challenges – in a clinical research setting. The feasibility study (at the time) used the Dexcom G5 CGM and a control algorithm built into the tubed pump (the disposable pump body from Asante, the durable controller has been customized by Bigfoot). Mean CGM glucose value through the study was 164 mg/dl, as participants spent 65% of time between 70-180 mg/dl, 0.9% of time <70 mg/dl, and 34% of time >180 mg/dl. These results are quite consistent with other AID studies, though of course, outcomes from this might look different in a longer trial. In presenting the poster, Chief Engineer Mr. Lane Desborough only referenced them once, noting that the company moved quickly to get an initial safety and feasibility trial done ASAP. Rather, the main attraction was to Mr. Desborough and co.’s modeling work – prior to the human study, over 100 million subject-days of simulation were performed to evaluate algorithm candidates, tune parameters, and predict performance across a range of conditions. (Yes, machine learning can run scores of clinical trials in seconds.) Amazingly, the extensive modeling and simulation work allowed the team to predict almost exactly what the outcomes of the human study would be, anticipating an identical 164 mg/dl mean CGM glucose value and ridiculously close 68% time between 70-180 mg/dl, 1% of time <70 mg/dl, and 31% of time >180 mg/dl. The CGM plots pasted immediately below – with the smooth, black S-curve representing the projected and the red clouds representing the actual outcomes – show how close the Bigfoot simulation projections were. The company has now characterized its algorithm extremely well in simulations, and all for $5,000 (Amazon Web Service cloud fees).

• Mr. Desborough indicated that running a simulated trial cost Bigfoot just pennies per patient-day, whereas a traditional in-clinic closed-loop trial runs tens of thousands of dollars per patient-day – that’s more than a million-fold difference! As an added benefit, the company avoided the need to put people through the discomfort of clinical trials while the algorithm development was still in progress.
  
  • Noted Mr. Desborough in a follow-up conversation with us: “The main takeaway for me is that simulation allows you to do things which would be impossible or impractical or unsafe to do in human trials. Control engineers perform experiments to develop models to be used in control algorithms. Once implemented, those control algorithms transfer variation from a place where it hurts (in our case, blood glucose) to a place where it doesn't hurt as much (basal insulin adjustment). Unfortunately “experimentation” and “closed loop control” have diametrically opposed objectives. The former seeks to maximize variation in the controlled variable (i.e., blood glucose) through carefully designed perturbations of the manipulated (i.e., insulin) and disturbance (i.e., carbs, exercise, stress) variables while the latter seeks to minimize variation in the controlled variable (i.e., blood glucose). Experimentation for the purpose of developing closed loop algorithms is thus caught in a dilemma: maximize variation for learning or minimize variation for safety and efficacy? Performing prospective experiments and characterizing behavior in simulations rather than human subjects allows us to avoid this dilemma.”
• As a reminder, Bigfoot expects to begin its pivotal trial next year with a next-gen factory calibrated Abbott FreeStyle Libre (launch possible in 2020, pending approval). Some have expressed skepticism that Bigfoot can’t possibly enter a pivotal so soon, as it only one feasibility study under its belt. This simulation data speaks to what the company has under the hood (hundreds of millions of patient days), and Mr. Desborough makes a strong case for cost effectiveness and predictive value with this approach. While it cannot simulate every use case, we believe modeling should play a larger role in the AID algorithm’s toolkit. We expect to hear more on the feasibility trial data and modeling tomorrow; Jen Block is presenting. Presumably Bigfoot’s pivotal trial will enroll a similar number of participants as Medtronic’s 670G pivotal, though we could imagine more or less would be included (more to capture a wider portion of the market and age groups; less because of the modeling approach).
• The simulations were run on Bigfoot’s vClinic, which simulates broad sources of blood glucose variation – change across populations, change throughout the day, change with activities and events, and change over time. In one such simulation that comprehensively included a missed meal bolus and an exercise challenge, 100 virtual subjects were sampled from the population distribution, each characterized by a unique combination of basal rate, carb ratio, insulin sensitivity factor, and open loop blood glucose distribution. Each subject was then simulated with and without AID system configuration setting mismatches – that is, with 27 different combinations of basal rate, carb ratio, and insulin sensitivity factor. Simulations even took into account unmeasured disturbance inputs, and included models for common pitfalls: carb counting error and CGM drift, dropout, calibration, and miscalibration. Wow!
  
  • Will simulations become more important in diabetes technology over time? As a reminder, Dexcom relied on simulation data at the G5 insulin dosing FDA Advisory Committee meeting last summer. At the time, many speakers (including FDA’s Dr. Courtney Lias) strongly supported use of the simulation models, even though the some of the panelists were quite confused by them. Though not the total package, Dr. Claudio Cobelli explained that the simulations are powerful because they allow for thousands of trials that directly compare SMBG and CGM in the same exact virtual user and with all else equal, and because they cheaply enable investigation in certain scenarios that would be dangerous and unethical to study in humans.

Smart Pens, Insulin Dose Titration, Clinical Decision Support, and BGM

Novo Nordisk Supplying NFC-Enabled NovoPen Echo & Tresiba Pens for NIH Study of TypeZero MDI Advisor

We learned that Novo Nordisk is supplying the NFC-enabled NovoPen Echo and a connected Tresiba pen for the ongoing three-month NIH-funded study (estimated n=132 type 1s ≥15 years old) of TypeZero’s inControl MDI Advisor at UVA, Stanford, and Mt. Sinai (Drs. Marc Breton, Stacey Anderson, Boris Kovatchev, Carol Levy, and Bruce Buckingham). Dexcom is also supplying CGM. We were aware that the NovoLog pen was piloting in limited fashion in Sweden, but this was the first that we can recall hearing (i) it is being used in the US; and (ii) there is also a connected basal insulin pen. We wonder if both pens are being used in other studies/pilots around the world, and whether there are near-term plans to add Bluetooth or submit to regulators in Europe or the US. Novo Nordisk is clearly deeply committed to connectivity and digital health, a point confirmed in our recent interview with CEO Mr. Lars Jørgensen and in a futuristic video at the HITLAB symposium a couple weeks ago. The control arm of the NIH study, expected to conclude in late May 2018, is CGM alone, and the primary outcome is time-in-range (70-180 during the day; 80-140 at night). As a reminder, the smartphone-based MDI Advisor (interface below) provides “smart” bolus advice, as well as exercise advice, sleep advice, hypoglycemia prediction, and eA1c (we’re not sure if it adds basal insulin titration). Dr. Buckingham displayed results from a small inControl pilot study in pumpers and MDI on Day #1.

• Dr. Boris Kovatchev also shared impressive data on his group’s dynamic, CGM-based hypoglycemia prediction. In one clinical evaluation, the algorithm classified future hypoglycemia risk in stoplight fashion (red=high, yellow=mid, green=low) – in the following hour, those with a green light at baseline had no glucose values <70 mg/dl, those with yellow had very little (<1% of time) <70 mg/dl, and those who had received a red alert spent nearly 25% of the time <70 mg/dl in the next hour, as well as ~13% at <60 mg/dl and 5%+ at <50 mg/dl. The power of this model to predict and allow the prevention of hypoglycemia is evident, and we love the simple green, red, yellow light interface – we’re not sure if that’s just for the trial/data presentation, or if it is also the way risk is conveyed to the user. Notably, the algorithm can also take into account other data, such as activity, presumably improving predictive power. We’re not clear on the commercialization pathway here – perhaps Dexcom would launch this as a decision support app for MDI users (see talk above from Peter Simpson).
  
  • The UVA team has also been working on SMBG-based decision support system, which relies on a model (“knowledge”) to fill in data gaps, for a number of years. We wonder how this will stack up to stronger predictive value from a CGM-based system.

• Dr. Kovatchev and team’s >20-year diabetes portfolio at UVA has amounted to 58 issued patents, 109 invention disclosures, and 309 applications of registered copyrights. Wow! Can TypeZero (either alone or with partners) execute and successfully commercialize some of this IP? So far, TypeZero has announced several partnerships and longer-term studies, but launches are still pending.

Dreamed Clinician Advisor Pivotal Beginning This Month; Pilot #2 Data

Schneider Children’s Prof. Moshe Phillip announced that the NextDREAM Consortium’s  six-month, multi-site pivotal trial for Dreamed’s clinician advisor (decision support) has begun as of this month, a slight delay from previous plans to begin in September. Prof. Phillip also shared data from the MD-Logic Advise4U Pilot 2 study (n=13) demonstrating that the Advisor once again results in comparable glucose control relative to expert care (we covered the first pilot data back in February at ATTD). In the study, patients were instructed by doctors – either based on their own clinical intuition or the Advisor’s recommendations – through two cycles of pump settings adjustments over the course of three months. There were no significant differences in time within range (70-180 mg/dl) between groups after three months, a good sign that software is performing as well as expert clinicians. Prof. Phillip did note a slight tendency for the Advisor to more effectively protect patients from hypoglycemia (see below). Both the control and Advisor groups included children, adolescents, and adults, and exhibited similar metabolic control at the study’s start (baseline A1c = 7.8%). The pilot data is very promising (non-inferiority in the bar, in our view), and we look forward to seeing the pivotal trial and ultimately a commercialized product. As a reminder, the pivotal trial will investigate the Advisor integrated within the Glooko platform, allowing providers to view the patient’s current therapy alongside suggested adjustments, including basal rates, carb ratio, correction factor, and active insulin time for pumpers. The Advisor also describes detected patterns related to patient behavior and insulin dosing using easily understood language. In his presentation, Dr. Phillip highlighted the “edit” feature on the Glooko platform, which facilitates physician alterations to the Advisor’s recommendations. As Prof. Phillip typically puts it, the Advisor is meant to be just another member of the care team, equivalent to knocking on the door of a colleague in search of a helpful tip for managing a patient. We love that positioning!

Topline Glooko MIDS Feasibility Results: Avg BG Drops 18 mg/dl, Readings in Range Up 9%; N=240 Study Underway

A poster presented more detailed findings from Glooko’s 14-day feasibility study (n=14 type 2s) showing use of the Mobile Insulin Dosing System (MIDS; a basal titration app) drives significant decreases in average blood glucose levels, as well as increased time-in-range and decreased time in hyperglycemia. Average blood glucose dropped 18 mg/dl (baseline 164 mg/dl), the proportion of in-range readings (80-180 mg/dl) increased by nine percentage points (baseline 64%), and the proportion of hyperglycemic readings (>250 mg/dl) decreased by 11 percentage points (baseline 14%), without a significant increase in the rate of hypoglycemic events. For all three metrics, variability decreased too. The rate of hypoglycemia readings (<70 mg/dl) did not differ significantly between the before and during study periods – it looked to be ~3% in both phases, though this was not quantified on the poster. (As we noted last week when the press release came out, this basal-only group with above-target average glucose was probably not seeing much hypoglycemia, hence little room for improvement.) Changes in in-range readings were positively correlated with titration cycle adherence, a great indication that the titration algorithm is efficacious. Fingerstick frequency was not reported, though we assume it was ~1-2 times per day. All participants were prescribed a personalized long-acting insulin (LAI) dosage treatment plan, ranging in complexity with titration periods varying from one to four days. At baseline, all of the people in the study were already on long acting insulin, so the results are an encouraging sign that adding MIDS brings additional benefits.

• The poster noted that a larger clinical study investigating the system for a longer duration is currently underway (recruiting per CT.gov). The study aims to randomize 240 type 2 patients to usual care (STEP WISE degludec algorithm) or MIDS, with a primary outcome of A1c change at 16 weeks and an expected completion date of November 2018. We learned last month at the Novo Nordisk-sponsored HITLAB Symposium that MIDS is still under FDA review following submission in mid-May – implying there has been some back-and-forth with the Agency, presumably on human factors. We’re looking forward to this product coming to market, perhaps with the larger marketing push of partner Novo Nordisk!

Verily’s Dr. Zisser Talks Current + Next Steps in AI Retinopathy Screening

Verily Diabetes Lead Dr. Howard Zisser provided an in-depth look at the company’s work in automated diabetic retinopathy detection, sharing that there are ongoing clinical trials in India. Notably, these studies go beyond the sensitivity/specificity of the deep learning algorithm (which is already strong, according to a ~year-old JAMA paper), but also on clinic workflow. Last week, we learned from Verily’s website that this is actually in partnership with imaging giant Nikon. Regarding technology vs. clinic workflow, Dr. Zisser said, “If you try to solve a problem without looking at the whole system, then you can be unsuccessful. We’re looking at ways to design image capture and workflow in the office. Today, many clinicians say they’re not interested because it’ll take up too much time.” It’s great to hear Verily is doing the necessary in-depth field work to ensure adoption success – how long does it take to get an image? Can you train a non-specialist to get an image? If you get a high-quality image, can you diagnose it quickly? – and not simply unleashing a powerful technology. The need is indeed dire: According to Dr. Zisser, India alone has a shortage of 127,000 (!) eye doctors, and 45% of patients suffer from vision loss before they are diagnosed. We’re excited to see Verily, IBM, and perhaps iDx launch products, particularly in nations with these types of dire shortages. In a similar vein, Verily is currently working on developing a screening device that is affordable, easy to use, not too big, but effective. In Q&A, Dr. Bruce Buckingham inquired if iPhone images were of sufficient quality – Dr. Zisser said, “I don’t know, but I’ll check,” and Dr. Buckingham said he would send a collection of images from Stanford to Verily for investigative purposes. It would be remarkable if these proved reliable for detection, as this would lower the cost and barriers to adoption even further. Then again, how would you ensure consistency in image quality? There might have to be an attachment that, for example, blocks out light and standardizes camera orientation and position. Also coming down the pike are algorithm feature updates (“Show me where the retinopathy is”) and expanded data sets to account for variation amongst different populations. Outside of the retinopathy realm, Verily is also undertaking deep learning studies in radiology and pathology. More broadly, we were glad to see Verily presenting separately at this year’s DTM, reinforcing its commitment to diabetes.

• Dr. Zisser displayed images of ARDA (automated retinal disease assessment), which conveys intensity and grading scores in a few seconds. We found a better-quality image online (below) than what we snapped during the session. The severity-indicating “diabetic retinopathy grade” graph at the bottom left as great to see, as an IBM researcher previously told us that Google/Verily’s algorithm did not have this. Along with IBM Watson, this means Verily’s algorithm now offers granular classification of stages of diabetic retinopathy, a nice way to track progression.

• We were also blown away by the algorithm’s ability to highlight problem areas in the images. In the below retinal fundus, moderately afflicted with retinopathy, the algorithm designated areas of damage in green. Dr. Zisser pointed out that it completely ignored the speck of dust in the center, something a human’s eyes would naturally be drawn to. 

• One analysis of over 30 ophthalmologists suggested a lot of inconsistency: within-grader consistency came out to ~65%, and between-grader consistency was only ~60%. In other words, even when trained clinicians are available, they are likely to be less reliable than algorithms available today, and certainly take much longer. Explained Dr. Zisser, “Thinking about how we as physicians were taught to recognize and diagnose things, it’s based on criteria – so many hemorrhages, so many fields. It’s straightforward, but is it the best way? Machines look at edge patterns, blocks of colors. It’s based on annotated material, so higher quality input equals higher quality output.” To those who argue it’s a “black box,” Dr. Zisser says “not really, you just have to ask the right questions of the right algorithms.” Even assuming that humans are adequate screeners, patients are not necessarily screened annually (even in the US), and even if they are, the proper follow-up isn’t always seen through.
• Tidepool VP Mr. Brandon Arbiter asked in Q&A where else in diabetes deep learning can be applied, to which Dr. Zisser replied: “We have to look in our menu of algorithms, and ask if there’s something that can match a given problem. For image recognition, the answer is yes – yes, yes, yes. For the diabetes space, we’re just starting to capture data. And I think a lot of the data we capture is incomplete – may ask a question and look at data set – we had CGM and activity data, but no insulin. There’s data missing. CareLink, you [Tidepool], Glooko – you have a lot of data. We want it to be high quality in format you can use. The main point is to ask the right questions, and design how you’re going to capture it.”

DTS Awaits FDA Response on BGM Surveillance Data; Repeated Study is Unlikely If No Policy Action Taken

Following Dr. Michael Kohn’s presentation of the illuminating DTS BGM Surveillance data (read our full report here), the Q&A session revealed that DTS is waiting for movement from the FDA before deciding whether to repeat the study. Dr. Klonoff suggested that the Agency’s response would ideally come in the form of punishing/inspecting poorly-performing meters. It’s difficult for the FDA to take an already-cleared device off the market, though perhaps there is also potential to influence payers or even Congress. Dr. Klonoff said he doesn’t necessarily expect immediate FDA action, but in response to Adam’s question (“Will you repeat this on an ongoing basis?”), he clarified, “if nothing has happened in a year or two, I don’t think I’d want to do another study.” While the study’s value is strong – showing that 12 of 18 meters did not pass accuracy criteria – Dr. Klonoff noted it was incredibly demanding and required four years to complete. Ultimately, the study was conducted not just out of academic interest, but also to affect public policy. If the FDA doesn’t/can’t take action, the data, regardless of its objective value, will not live up to its full potential to improve patient safety. Dr. Klonoff believes the study does “deserve to be done again,” especially given the landscape’s dynamic nature – a couple of the meters included in the study are actually off the market now. Dr. Kohn agreed, claiming that repeating the study annually or every other year would be optimal, but that, “if you don’t take action, there’s no point in measuring the issue again.” We agree with this analysis! Dr. Alberto Gutierrez, who just recently retired from his post at the FDA, mentioned that the Agency is interested in looking into the DTS study, but cautioned that taking already-cleared products off the market is a lengthy and difficult process. We too hope to see the FDA or at least payers (especially Medicare!) take some action to punish inaccurate meters – it is our view that if a product wouldn’t get approved today, but was approved years ago when standards were lower and options were fewer, then it has no business being on the market.

8,000 Suggestic App Users; Food Personalization and Insight for More Precision Eating

Mr. Victor Chapela, CEO of Suggestic, highlighted three key features he believes are critical for “precision eating” or “food as medicine”): (i) personalization; (ii) actionable insight; and (iii) know-how. The Suggestic app, which recently won the Health 2.0 Launch competition and leverages machine learning, aims to help people eat their diet of choice – see screenshots below. Still in beta, Suggestic currently has 8,000 users. Mr. Chapela noted that there is already lots of knowledge on how to eat well; however, there’s not enough “how to” and a community-centric marketplace for people to “shop around” for nutritional plans. Mr. Chapela hopes to change this with better personalization. Suggestic provides a variety of diets (e.g., paleo, low carb, Mediterranean, DASH, ADA), allows users to read reviews, find foods to avoid, recommends recipes, helps with ordering in restaurants, and even overlays augmented reality on a restaurant menu – very cool! The company also has some promising partners that might help personalize dietary choices based on genetics or microbiome (23andMe, Helix and Pathway Genomics). In the background, Suggestic creates hidden chains of activity, linking users’ food choices with their health goals like weight loss or A1c reductions. The app learns which sequences of activities are most likely to lead to achievement of user goals. Deep neural networks are utilized to filter for optimal ingredients and nutritional recommendations. These algorithms (the know-how) will also be made publically available, a nice open ecosystem move. Things are still early, but many seemed impressed with the app – will users find enough value to take it out multiple times a day to determine if food is ok to eat and then log it? (This remains difficult, even for highly motivated individuals.) How will Suggestic keep people engaged long-term? Or better yet, how long using Suggestic would it take to train and motivate someone to “self-manage” food as medication? For more details on the app, read our profile from Health 2.0 here.

Dr. Bruce Buckingham on Smart Pens; Companion Medical On Pace for 2017 Launch; TypeZero Pilot Data

Stanford’s Dr. Bruce Buckingham was very excited to discuss the long-awaited smart pen, commenting that he believes Companion Medical’s InPen, which we’ve confirmed is still on track for a 2017 launch (two months left!), is going to be a “game-changer.” Dr. Buckingham showed a number of new-to-us screenshots of the InPen app (below), including the bolus calculator, and the “reverse bolus calculator” (input: blood glucose; output: additional grams of carbs to consume). In his review of the landscape, Dr. Buckingham called attention to the Timesulin dose capture device (now a part of Bigfoot), and the Echo Pen from Novo Nordisk (piloting in Sweden). Instead of arguing the usual case that clinicians need data from connected pens because it’s a huge gap in clinical care, Dr. Buckingham showed it. He displayed a series of sensor and pump downloads showing post-prandial excursions. “You might think you need a more aggressive insulin:carb ratio,” he said, “but it’s the wrong thing to do.” He then pressed the clicker and the bolus size and timing data appeared on the bottom of the screen. In each example, it was clear that making the patient bolus more aggressively would’ve been a very bad idea, because it was a matter of timing; they were bolusing after they had already started eating. Having this information makes it much easier (read: possible!) to make therapeutic decisions. Wearing a different hat, Dr. Buckingham noted that connected pens also make the job of a researcher much easier, because it’s very difficult to do a study in diabetes if you don’t know when and how much insulin was given.

• Dr. Buckingham also briefly flashed pilot clinical trial data from the TypeZero open-loop decision support system (DSS) pilot clinical trial in pumps and MDIs on the screen. Based on the (confusing) figure below, the TypeZero system seems to have reduced hypoglycemia and brought a tighter range of glucose values in the study population. Impressively, TypeZero’s decision support offers smart bolus calculation, hypoglycemia prediction, exercise and sleep advice, and in silico therapy optimization, and eA1c. Dr. Buckingham added that his group is conducting an ongoing clinical trial, along with groups from UVA and Mt. Sinai, with TypeZero’s inControl MDI Advisor. This is the first open-loop decision support system connected to a sensor that he has worked with.

• He also briefly reviewed the Esysta smart pen that recently launched in Germany. In one Esysta clinical trial of 215 participants (mean age: 60 years; 81% T2D), after ~14 months of observation, A1c reportedly dropped 0.9% (baseline: 8.7%). In the type 1 participants, mean total daily dose also decreased. Dr. Buckingham noted that the patients in the Esysta study who had more interactions with their providers saw the biggest drops in A1c, underscoring the concept that technology is best leveraged as a complement to the care from a provider. Given the scarcity of trials in this area, as well as discouraging results in some early trials with older memory pens (e.g., Danne et al., 2012 with Lilly’s HumaPen Memoir), we hope to see this field evolve as rapidly as closed-loop has. Connected pens seems like an exciting frontier for payers and pharma, who will get far better data on how drugs are used in real life.

Insulin, Insulin Delivery, and Insulin Monitoring

Lutz Heinemann Shares Early Concerning Data: Highly Variable Insulin Concentrations in U100 Regular+NPH Vials Procured at Pharmacies

Prompted by the French-led inspection of Biocon, Dr. Lutz Heinemann generated a stir by calling into the question the quality of insulin that end users are actually injecting: He presented preliminary results from a basic mass spectrometry study in which colleague Dr. Alan Carter et al. found that only one of 18 U100 regular and NPH samples procured at different pharmacies approached a concentration of 100 units per ml – the others were much lower (see figure below). All of the nine regular insulin samples hovered between just 13.9-28.7 units per ml (suggesting someone could be injecting 1/8 as much insulin as he/she thought!) while the NPH samples were much more variable (equally concerning), ranging from 35.1-94.2 U/ml. FDA requires that the concentration of U100 insulin is at least 95 U/ml before it leaves the manufacturer, and Dr. Heinemann doesn’t doubt that the manufacturers are compliant. Rather, his intuition is that the supply chain may not working as expected – at some point during the vial’s journey from manufacturer cold room to pharmacy, something may be going awry. Dr. David Rodbard suggested that perhaps the vials get “beat up” during transit, which could cause degradation. Whatever the reason, Dr. Heinemann called for a deeper analysis into the issue (he also acknowledged it could be measurement error), causing meeting organizer Dr. David Klonoff to wonder – is there a need for an ongoing Insulin Post-Market Surveillance Program (similar to the recently reported BGM Surveillance Program)?

• The study’s early findings caused a lot of hallway chatter in the subsequent coffee break – mostly in the form of shock (Dr. David Kerr referred to it as “the scariest data of the meeting,” but there was also a healthy dose of skepticism floating around. People called into question the group’s analytical methods, sample preparations, vial handling, etc. Dr. Heinemann, aware of the possible implications of this study, was also healthily skeptical: “I encourage other people to repeat such measurements in order to see – have we done anything wrong? Probably, I don’t know. You’re always skeptical about yourself when you do this the first time. The best explanation we see is the need to look into the details of the cold chain. [Dr. Carter] and I would be happy to have more brains working on this.”
• At the end of the day, insulin vial quality variability gets heaped on to the list of factors that contribute to uncertainty in diabetes therapy. Is this a real issue? We’ll be interested to follow this at subsequent meetings, and we wonder if the data below also applies to analog insulin. Presentations on continuous insulin monitoring later in the day also made us wonder about the possible benefits of quantifying circulating insulin levels, and therefore characterizing insulin absorption and quality status – a metric Close Concerns hereby coins “IAQS” (rhymes with “kayaks”).

Dr. Zhen Gu Introduces New Lab Projects – Smart Glucagon Patch, Artificial Beta Cell, More

UNC/NC State’s Dr. Zhen Gu introduced a number of new projects his lab is working on (including a smart glucagon patch for hypoglycemia prevention and an artificial beta cell) and presented new data on existing projects (red blood cell-tethered insulin). Dr. Gu is best known for his early-stage work on developing a smart insulin patch. What’s next for his lab? (i) Optimize smart insulin patch with stability, carrying capacity, response speed, and biocompatibility; and (ii) test the smart insulin patch on pigs with CGM. It seems as if every time we hear him talk, Dr. Gu has another host of ideas to share – and it usually comes with preliminary data. One problem, as UCSF’s Dr. Gerald Grodsky pointed out, is that the work is high potential, but there have yet to be studies in larger animals. Dr. Grodsky is concerned about sensitivity to falling glucose levels. Dr. Gu responded that he has been running a larger animal study “for a couple months with encouraging preliminary data, but it needs further validation and optimization.”

• The other patches under development are: (i) a smart glucagon patch for hypoglycemia prevention (glucagon is released from the microneedle array when insulin concentrations get too high; see below) – hopefully the team can learn from Zosano’s failures with microneedle patch-delivered glucagon; (ii) a smart cell patch, in which external beta cell capsules which rest on top of the microneedle patch; picture); (iii) an “anti-obesity” patch, which aims to convert white fat into brown fat and ideally improve diabetes too. As a reminder, the transcutaneous microneedles are 600 um-800 um long (not long enough to reach nerves, so essentially pain-free; see pictures here).

• Recently, Dr. Gu has been developing synthetic artificial beta cells, where he modifies a signaling process: When glucose comes in through a channel, pH is locally reduced, causing polymers on the surface of insulin-containing vesicles to unbind, exposing other proteins on the surface that allows the insulin-containing vesicles to fuse with the “cell” membrane, spilling their contents outside. Dr. Gu displayed preclinical data (below) showing that the fully-intact artificial beta cell induces a rapid fall in blood glucose that lasts five hours before ramping back up (presumably in mice treated with STZ). Work on this project was published in Nature Chemical Biology last month, with Dr. John Buse listed as a co-author.

• Dr. Gu has also published his first study of “hijacking” red blood cells for smart insulin delivery. In a mouse with STZ-induced type 1 diabetes, on the left below, the red blood cell-bound insulin is sufficient to lower blood glucose for a longer period of time than glycated insulin alone or insulin and red blood cells injected together; and on the right, it is clear that the method yields glucose-responsive insulin release. We’d love to know what the next steps are in this study. This work was published in Advanced Materials in March, again with Dr. Buse as a co-author.
  
  • The basic principle, as we understand it, is that red blood cells are isolated from a donor and linked to a glucosamine-insulin complex. After being injected intravenously back into the donor, the glucosamine-insulin complex dissociates from the blood cell and binds GLUT receptors. In hyperglycemic environments, the insulin then leaves the bound glucose molecule to complex with circulating glucose, where it can then lower blood glucose on a systemic level.

Diasome Prandial Insulin Slated for Late 2021 FDA Approval; Basal in Phase 2 Into 2020

Diasome’s Dr. Doug Muchmore shared a slightly delayed timeline for the company’s three ongoing phase 2 trials of its Hepatocyte Directed Vesicle (HDV) insulin lispro – with phase 3 in 2019-2020, an NDA filing in 2021, and possible approval in late 2021. He also gave timing on two phase 2 studies of an HDV basal insulin: a dosing study in late 2018 (ending in early 2019), paving the way for a phase 2b (ISLE-2) study to begin in 2019 and wrap up in late 2020. Dr. Muchmore noted that there is no CVOT requirement for either insulin, as it stands. Both are delivered subcutaneously. As a reminder, Diasome’s technology consists of nano-vesicles added to insulins to target insulin to the liver. There was substantial chatter at this meeting about the benefits of supplying insulin to the liver, better mimicking physiology and overcoming some of the big drawbacks of peripheral delivery. Will Diasome be the first to bring something to market? Will it seek a larger insulin player as a partner for phase 3 or commercialization?

Aptitude Developing Fingerstick and Continuous Insulin Monitoring; Dr. Kerr on Why Continous Insulin Monitoring Would Be Clinically Beneficial

In a new-to-us area of diabetes tech, Santa Barbara-based Aptitude is developing a product to monitor insulin levels in the blood, both as a fingerstick and as a continuous sensor. Aptitude is a spinout from UCSB and uses next-generation “aptamers” immobilized on an electrochemical sensor. When insulin binds to the specifically tailored sensor, it causes the “aptamer” (a synthetic antibody) to change shape. The product has shown feasibility with a chemotherapy drug, and the team has done a lot of work on measuring insulin. Near-term it is developing the INSIGHT “personal insulin meter” – an episodic insulin sensor that exploits a high performance aptamer (see picture below). Just like a BGM, a fingerstick measurement would allow someone to measure insulin concentrations on the spot – test time is a fairly lengthy “<2 minutes,” though we assume this could be improved. Dr. Ferguson noted the system is low cost, compatible with established glucose monitoring technology (combination with strips?), and can currently differentiate between prandial and basal insulin analogs – the current version can only measure Novolog, Humalog, and Apidra, though another aptamer could be developed for basal insulin analogs. He showed a prototype of the fingerstick meter, and work is ongoing to complete a manufacturing-ready prototype, optimize the sensor, and deploy a development kit in clinical research settings. Notably, Yale’s Dr. Eda Cengiz is a clinical collaborator, where work will proceed to demonstrate a use case – utilizing patient-specific insulin pharmacokinetic measures (we assume relevant for closing the loop). The acknowledgment slides also listed Drs. David Kerr and Howard Zisser. We’ll continue to watch this early technology – as Dr. Kerr’s enthusiastic commentary and Aptitude’s slide notes (below), there is some interesting clinical value in insulin monitoring for closing the loop/dose titration, better understanding how insulin is working, detecting/monitoring hyperinsulinemia in type 2 diabetes, etc. The bigger question is whether the additional value will be worth paying for, given the current state of underpenetrated CGM use and shrinking BGM margins.

• Sansum’s Dr. David Kerr also provided a concise list of reasons why continuous insulin monitoring might be beneficial:
  
  • Add value to technologies (e.g. closed loop; smart pen/CGM-driven insulin titration)
  • Help figure out why CSII and MDI have different outcomes
  • Known when to intensify to insulin therapy
  • Help overcome clinical inertia
  • Make clinician’s job easier in figuring out why real-world efficacy isn’t as good as it should be
  • Ameliorate some of the psychological consequences associated with diabetes
  • When to start insulin in type 2 diabetes
  • Optimizing once-daily basal insulin
  • “If I could measure insulin, we could wind back and have clinical discussions with the individual about determinants of health and ways of dealing with it”
  • Precision medicine (e.g. Why do different races have different outcomes?)
  • Prediction: Knowing insulin levels will allow us to use less insulin (Joslin medalists tend to use less insulin – safer?)
• Aptitude’s slide deck shared a similar list of potential clinical indications for insulin monitoring:

First Look at Screenshots of Well-Designed U500 Lilly/Insulet OmniPod PDM

Insulet Medical Director Dr. Trang Ly showed screenshots of the U500 Lilly Omnipod PDM for the first time publicly and explained design considerations for the type 2 population. She explained how, after iterative UX development and human factors research, the user interface has been revised for simplicity, with a condensed home screen and easier navigation. Specifically, text size and contrast have been adjusted for readability, and certain more-complex information features have been removed or de-emphasized. Key information, such as last bolus and last blood glucose are displayed on the home screen, and time/insulin left in the Omnipod appear on the PDM (both images below). We noticed the U500 home screen looked quite different than the U100 Dash PDM we saw at ADA, which is intentional – these are specific for the U500 pump, which will be a separate product to Dash, hence the deliberately different color scheme. The greater simplicity of this U500 version is excellent. Insulet and Lilly have also developed a U500-specific syringe that reflects the actual units of insulin, eliminating the need for mathematical conversion. Based on the company’s user research, these adjustments will greatly benefit the target type 2 population – many of those interviewed were not familiar with insulin on board (they understandably thought it was how much insulin was left in the pump reservoir), duration of insulin action, correction factor, and insulin:carb ratio. Most who were already on U500 insulin didn’t fully understand why or know how it was different from what they had previously used. Disturbingly, the surveys revealed that many patients had limited training on their pumps, knowledge of just the basic bolus function, and some wouldn’t even touch the pump out of fear that they would “do something wrong.” As Dr. Ly said, they were “really petrified” of some of the more complex features. It is amazing to hear Insulet unearthing these insights from people with diabetes, designing for them, and then talking candidly about them. Of course, not all type 2s fall into this camp, but these anecdotal findings underscore the echo chamber effect we are increasingly reminded of – the “average” person with diabetes is a lot different than the people sitting in the audiences of digital health/diabetes tech conferences. At the same time, Dr. Ly and team seem to have totally embraced the valuable design thinking, iterative approach to patient-centric design to ensure safe and effective use. Dr. Ly didn’t present any day results from the recently-completed phase 3 trial – data is currently being analyzed, and per Dr. Ly’s AADE remarks, will hopefully be presented at ADA 2018. The U500 PDM is expected to launch in 2019, per Insulet’s last update.

• As we’ve come to expect, Dr. Ly noted that OmniPod is the only approved insulin delivery device on the market not reimbursed by Medicare. She acknowledged that there would be many likely U500 PDM customers in that population, and assured that the company is working on it. The 3Q17 call today shared confidence from CEO Patrick Sullivan, but did not give any timing update. One of the sticking points is whether the OmniPod should fit into Part B or Part D; Insulet is comfortable with either.
• Lilly’s Ms. Jennal Johnson and Dr. Ly actually split the presentation time in their discussion of the impactful partnership. The collaboration was announced ~4.5 years ago (!) and has been pushed back a few times. We’re glad to see the finish line (that is, launch) coming into view, as concentrated insulins in a pump (on-label) is a true unmet need; Dr. Ly shared that 25% of overall U500 insulin use comes from pumps today!

Alt Insulin Delivery Update: Oramed t3-Month Study of Oral Insulin Soon; Dance Completes 2 PK/PD Studies of Inhaled Insulin

Oramed CSO Dr. Miriam Kidron shared that the company will soon test oral insulin candidate ORMD-0801 in a three-month study, which will “hopefully bring us to phase 3 and registration.” We also saw preclinical data on an oral insulin+GLP-1 agonist candidate (ORMD-0901+ORMD-0801). As we understood it, the standalone oral insulin piece (ORMD-0801) is still years away in the best case scenario (won’t be on the market until after 2020), and an IND for the standalone GLP-1 agonist will be submitted soon. FDA has also requested food effect trials for the insulin product, which Oramed plans on conducting this year (i.e. how does the drug interact with food quantity and content?). We last saw phase 2b results (n=180; 28 days) for the insulin candidate in August. The trial showed a significant difference in the unconventional primary endpoint of mean change in nighttime glucose from run in (1.66 mg/dl for the ORMD-0801-treated group vs. 13.70 mg/dl for placebo, p=0.0117), as measured by a CGM. (We cannot ever recall a trial using such an endpoint.) As for the insulin+GLP-1 agonist pill, a small study of combination treatment in swine showed a solid glucose-lowering synergism between the two (see below). This is our first time hearing of an all-oral insulin+GLP-1 agonist product, and though it is clearly a long way away, the idea seems compelling if bioavailability and cost and efficacy are there. (Big Ifs, especially given how long Oramed has been working on this.) During Q&A, Dr. Kidron emphasized the decreased hypoglycemia risk (due to portal delivery) of oral insulin, and claimed that her company has an advantage over Biocon –  Biocon tweaks the insulin molecule, while Oramed simply packages and delivers it. That said, she would be very happy if Biocon succeeds, probably for reasons of class awareness.

• In other news, we learned that Dance Biopharm has now conducted two PK/PD trials of its inhaled (liquid) insulin 501. Results suggest the formulation is slower than Afrezza up front (though more rapid onset than subcutaneous analogs) and has a longer tail, potentially making it a better option for coverage of mixed meals. The timeline we heard at DTM 2015 has obviously been pushed back – the company was previously planning for a phase 2b study in 2016, four phase 3 studies in 2017 (two in type 2, two in type 1), submission to EMA and FDA in 2019, and approval in 2020. We are surprised to hear that the product is still in development, given the challenges Afrezza has faced and the direction insulin pricing is heading.
• Said Dr. Lutz Heinemann: “If you are an insulin company and you aren’t thinking about having an automated system, you are stupid.” Dr. Heinemann said that oral insulin companies are apparently working with closed-loop researchers (as an adjunct therapy) and have data. An AACE symposium did share that groups at Yale and UVA are testing adjunctive Afrezza in the automated insulin delivery setting.
• On inhaled insulin, Dr. Heinemann doesn’t think it’s a dead horse, but does it have a bright and straightforward future? He’s not sure. He chalked up the Sanofi/Mannkind debacle to a host of factors, including a restricted label and poor marketing and advertising, but noted that Mannkind is active on the market on its own now and that patient satisfaction with inhaled insulin is very high. As a backdrop to his comments, in 2Q17, Afrezza sales grew 25% sequentially to $1.5 million.

-- by Brian Levine, Maeve Serino, Adam Brown, and Kelly Close