DTM 2019 (Diabetes Technology Meeting)

November 14-16, 2019; Rockville, MD; Day #1 Highlights - Draft

Executive Highlights

  • The 19th annual Diabetes Technology Meeting kicked off this morning in Rockville, MD! See our highlights below and our preview for a look at Friday and Saturday.

  • Connected insulin pens and decision support were discussed throughout the day, headlined by Novo Nordisk announcing a 2Q20 launch start for its NovoPen 6 and Echo Plus pens. Presumably the launch will begin in Europe, where the devices already have CE Mark, before coming to the US. A reusable connected pen attachment for Novo’s disposable pens is now expected to launch in 2021, behind the initially anticipated launch and a welcome respite – the company should absolutely take its time to get this right (there appears to be more nuance to the disposable attachment,). Additionally, a roadmap slide for Novo showed three grayed-out “digital therapeutic” projects, something the company is working on “very actively.” Sansum’s Dr. David Kerr also gave an interesting and optimistic talk on this emerging category.

  • There were CGM updates aplenty, as Dexcom, Medtronic, and Senseonics all shared R&D efforts to improve CGM performance further – wow the field is ambitious and has come such a long way. Dexcom’s Mr. Peter Simpson presented on a modified G6 algorithm and early field data from a new G6 adhesive; there were unfortunately no new updates on G7. Medtronic’s Dr. Robert Mucic gave a look at the company’s adhesive selection process for its next-gen CGM (Synergy?), including some 14-day tests. Senseonics shared a look at its next sensor design (same size, more hardware), its plans for increasing Eversense wear time to 180 and then 365 days, and real-world data from 945 European Eversense users across four sensor cycles (TIR: 63%-65%, GMI: 7%). This was recently published in Diabetes Technology and Therapeutics – “Longitudinal Analysis of Real-World Performance of an Implantable Continuous Glucose Sensor Over Multiple Sensor Insertion and Removal Cycles.”

  • In decision support, a field where we expect to see increasing investment and further progress, OHSU’s Dr. Jessica Castle shared some details and screenshots for the Helmsley-funded “DailyDose” app for CGM+MDI users. The app will include a “smart” bolus calculator, recommendations for insulin:carb ratios, correction factor, and basal dose, hypoglycemia predictions, and more.

Greetings from the Bethesda North Marriott and DTM 2019! Today was a pre-conference day before the main show starts tomorrow – see our highlights below and read our preview here

Top Six Highlights

1. Novo Nordisk’s Connected NovoPen 6 and Echo Plus to Launch in 2Q20, Removable Pen Attachment in 2021; Decision Support in Pipeline

In a brief update on Novo Nordisk’s connected pen strategy, we learned that the already CE-Marked NovoPen 6 and NovoPen Echo Plus pens will launch in 2Q20, presumably starting in Europe where they already have regulatory approval. The timing is in line with the “2020” timeline given in Novo Nordisk’s most recent update, and about a year back from the “early 2019” goal given when the devices were first announced – it’s important to get the product and manufacturing right here, so we appreciate the cautious approach. As expected, the reusable NovoPen 6 and Echo Plus will display the last insulin dose and time on their ends, have an 800-dose memory, and five-year battery life. Data from the pens can be downloaded with NFC and the pens are compatible with any Novo Nordisk insulin cartridges, human and analog. The NovoPen 6 will allow adjustments down to 1 U with a maximum 60 U dose, while the pediatrics-targeted Echo Plus will allow adjustments down to 0.5 U with a maximum 30 U dose. We also got a look at the reusable pen attachment designed for Novo Nordisk’s disposable pens. That device is now targeted for launch in 2021, and while behind the initially anticipated launch, we’re happy to see decisions against rushing this to market and we’re glad Novo Nordisk is taking the time that it needs to get to market. It appears Novo Nordisk will launch its own app for that product, whereas the NFC pens will be more focus on in-clinic download. Presumably there is much more complexity with the Bluetooth-enabled add-on attachment. There’s so much room for fantatic apps we hope it is investing in this area and taking the time required to get this right. The first insulin pen was launched in 1985 – we’ve had over 30 years of pens that are not connected and we believe the broad diabetes ecosystem prefers organizations to take the time needed to make sure this is the best possible development and launch rather than rushing it. We also appreciate that this is a new arena and that timelines are challenging to make since there is much ‘unknown’ that can emerge.

  • Conspicuously grayed out in the roadmap above are three “digital therapeutic” projects. Dr. Anders Toft, Novo Nordisk’s Corporate Vice President of Commercial Innovation briefly referenced the projects as something the company is working on “very actively”: “That is where we see a major future promise with the data that comes passively from smart pens and connected CGM/BGM – leveraging that with algorithm-powered aps that can guide a patient safely and effectively to [better management].” Novo Nordisk already has an impressive list of data integration partners for its smart pen devices: Roche/mySugr, Dexcom, Glooko, Abbott, and Medtronic. Dr. Toft emphasized that these partnerships were “non-exclusive” and that the “data will belong to the patient.”

  • Dr. Toft presented results from the 12-site Swedish pilot study (n=94) with CGM (Dexcom G4 or Abbott FreeStyle Libre) and NovoPen 6 (results were first shown at two posters at ADA 2019). Two-weeks of CGM metrics at follow-up (14 days after the final clinic visit) were compared to two-week baseline metrics (14 days following obtaining the pen). Compared to baseline, mean time-in-range improved from 38% to 46% (+1.9 hours/day), driven by time >180 mg/dl decreasing from 49% to 42% (-1.8 hours/day). 81 adults were included in the adherence analysis, which showed a very impressive 43% fewer missed meal boluses (baseline: 0.74/day). We are also struck by how much better patients can do than 46% time in range – there must be multiple interventions that can go along with therapeutic and technological ones (apps like Under My Fork, etc. – though it’s easiest to use these with CGM, connected blood glucose monitors work also).

2. Dexcom G6 New Adhesive Patch and Modified Algorithm Launched; No New G7 Updates (late 2020 launch)

Dexcom’s Mr. Peter Simpson kicked off DTM 2019 with a few updates on G6:Mr. Simpson shared some initial field data (n=~2,500) showing a 43% relative improvement in 10-day patch survival rates using a new patch. At Keystone, Dexcom EVP Andy Balo shared that Dexcom had filed a new adhesive with the FDA. Based on the graph shown, the new patch, which has apparently already launched, shows a 10-day survival rate of ~95%, compared to ~90% with the original patch.

  • A modified G6 algorithm has shown a 24% relative improvement in data availability (i.e., reduced sensor errors where data is not displayed). Preliminary analysis from 310 subjects showed data was available 98.3% of the time with the original algorithm and 98.7% of the time with the modified algorithm. Data availability on the 10th day of wear was improved from 96.6% to 98.5% (a 56% relative reduction in data unavailable errors). The modified algorithm has not yet been submitted for approval.

  • An unpublished study (n=78 type 1s) showed today suggested that G6 has strong accuracy performance with one-hour warmup and out to 14 days. G6 currently requires a two-hour warmup and automatically shuts off after 10 days. Between hours 1-2 of G6 wear (n=162 matched pairs), overall MARD was an impressive 9.9% and 93.2% of values were within 20%/±20 mg/dl of YSI reference. At day 10, MARD was 9.2% with 93.7% within 20%/±20 mg/dl. Accuracy was not significantly diminished at day 14, which showed a MARD of 9.2% and 91.9% within 20%/±20 mg/dl. For reference, Dexcom advertises a MARD of 9.0% in its G6 User Guide. We do not believe Dexcom plans to go for 14-day wear for G6 in advance of G7.

    • G7, however, is planned to have longer wear and faster warm-up. The results of this unpublished study suggest achieving these goals shouldn’t be a huge issue, even using the same chemistry and algorithm as the G6. G7 will obviously need to meet iCGM benchmarks out to 14 days, and the adhesive will reliably need to reach that length of wear. Many Dexcom G5 users wear their sensors for longer than 10 days by restarting the sensor; the G6 has a mandatory shutoff as part of iCGM special controls.

  • Mr. Simpson reiterated the planned focus for Dexcom G7 and the targeted launch of “late 2020.” He outlined three key areas for G7: (i) making the device more convenient to wear (i.e., smaller); (ii) simplicity and ease of use (“just a few steps from opening package to getting CGM data”); and (iii) reducing cost. Last week, we heard Dexcom and Verily were making “final tweaks” to the design. The slide below is taken from previous Dexcom presentations; we should hopefully see an updated look at the hardware at JPM in January.

3. Medtronic Shows 14-Day Patch Survival Study for CGM “Prototype”; Could Synergy Have 10 or 14-Day Wear-Time?

Increasing wear-time was a major theme throughout Thursday morning’s CGM session, and Medtronic’s Dr. Robert Mucic shared data from the patch design selection process for Medtronic’s next-gen CGM with studies out to 14-days. The studies were done with multiple adhesives and four different adhesive patch sizes, using a “representative payload” with the same size and profile as the planned CGM. Medtronic gathered user input during an internal study on level of skin discomfort, adhesive “edge lift,” appearance acceptability, and “device awareness during wear,” on eight combinations of adhesive and patch size. While skin discomfort, appearance acceptability, and device awareness during wear were all similar, there was significant differentiation in edge lift. Following patch removal, there were also significant differences in the level of adhesive residue and clean-up required. This helped Medtronic choose three materials for an external study with 28 people in a “Northern State” (mid- to high- 70s temperature, upper 80s humidity) and 31 people in a “Southern State” (high-80s to low-90s temperature, low 90s humidity). The hotter, more-humid weather showed one material clearly performed worse than the others over the 14-day wear period. Finally, a larger, multi-site study (n=310) helped differentiate the final two chosen adhesives; the 14-day survival rate for the best-performing adhesive appeared to be around 85%. Great to see Medtronic thinking so deliberately about adhesive!

  • Notably, the picture of the “one-piece sensor and transmitter prototype” was identical to the picture we’ve seen for Medtronic’s fully disposable, 7-day, Synergy iCGM. Dr. Mucic expanded a bit on the form factor of the device, emphasizing the radial symmetry as making the device easier to insert (users won’t have to worry about orientation). Given the studies Dr. Mucic described tested adhesive patches out to 14-days, could Medtronic potentially launch Synergy with a longer wear time of 10-days or 14-days? Synergy is targeted for FDA submission in November 2020-April 2021 and launch by ADA 2021.


4. “About Half” of Eversense Sensors Removed at 180-Days Would Support 365-Days of Performance; Real-World Data from Europe Shows ~64% TIR, ~12% MARD vs. BGM Reference

Senseonics’ Mr. Alex Ghesquiere shared a quick look ahead at Senseonics’ plans for the implantable Eversense CGM, noting that “current R&D clinical tests” are already ongoing with Eversense up to 365-day wear. Additionally, he shared that “~50%” of current Eversense XL sensors that are removed at 180-days could actually support 365-days of wear. Currently, Eversense is approved for 180-days in Europe and 90-days in the US; enrollment for the 180-day US PROMISE trial just completed, with study completion expected in 1Q20 and launch of the 180-day sensor by “the end of 2020.” Extending sensor wear out to a full-year will require some chemistry and hardware modifications, primarily to prevent oxidation from degrading its glucose indicator monomer, TFM. Currently, the Eversense sensor has a dexamethasone coating, an anti-inflammatory steroid, to reduce oxidative species around the sensor. Mr. Ghesquiere shared that Senseonics is also considering providing alternate oxidation sites, among other methods, to further limit degradation of the TFM. Lastly, Mr. Ghesquiere presented a new sensor design, which will begin “clinical testing” starting this month. The new sensor will maintain the same size, but pack significantly more inside. The new design includes two integrated chips with four excitation LEDs each, compared to a single excitation LED in the current sensor. The improved sensor will include two hydrogels with indicator chemistry (rather than one). According to Mr. Ghesquiere, the new sensor design will enable a reduction in calibrations (Eversense currently requires two fingersticks/day), longer sensor life, and improved system accuracy.

  • Mr. Ghesquiere also presented data from the recently published real-world data from the first 945 European users to complete 4 cycles of sensor wear. The sensor MARD was between 11.5% and 12% for the four sensor cycles, compared to BGM calibration (n=705,462 paired points!). Across the four cycles, user time-in-range was between 63% and 65% with ~5% time spent below 70 mg/dl. Mean GMI was right around 7% and median transmitter wear time increased slightly from 83% in the first sensor cycle to 86% in the fourth sensor cycle.

Cycle

Sensor Cycle 1

Sensor Cycle 2

Sensor Cycle 3

Sensor Cycle 4

Mean sensor glucose

157 mg/dl

158 mg/dl

157 mg/dl

157 mg/dl

%CV

35%

35%

35%

36%

GMI

7%

7%

7%

7%

Time <54 mg/dl

1.1%

1.2%

1.2%

1.3%

Time <70 mg/dl

4.6%

4.7%

4.8%

5.0%

Time-in-range

64.5%

63.2%

63.7%

64%

Time >180 mg/dl

30.9%

32%

31.5%

31%

Time >250 mg/dl

8.1%

8.8%

8.6%

8.6%

Median wear time

83%

84%

85%

86%

5. Dr. Jessica Castle Shares Helmsley-Funded Early-Stage Decision Support App “DailyDose” for CGM + MDI; Plans for n=20 Pilot Study

Dr. Jessica Castle (Oregon Health Sciences University) shared promising details regarding a new decision support app “DailyDose,” under development by OHSU and University Health Network – check out the user interface below. Using input from Dexcom G6 and Companion Medical’s connected pen, InPen, the DailyDose app integrates data to generate a comprehensive collection of outputs including:

  • A “smart” bolus calculator (presumably a CGM-based bolus calculator – something no company has gotten cleared yet);

  • A machine-learning recommender engine that gives weekly recommendations for insulin:carb ratios, correction factor, and basal insulin dose (this is so needed!);

  • An “Insight” page that explains to users why a recommendation was made;

  • Hypoglycemia prediction alerts (30-minute prediction horizon); and

  • Carbohydrate intake and insulin dose adjustment for exercise (based on JDRF’s PEAK guidelines).

We first heard about DailyDose at ADA 2018 as a decision support app co-developed by University of Toronto’s Dr. Joe Cafazzo and funded by Helmsley Charitable Trust. Recommendations are specifically programmed to prioritize improving time-in-range (TIR) and reduce hypoglycemia, in conjunction with a post-prandial hyperglycemia prevention algorithm (ALPHA). In terms of quality, a healthcare provider first sets the “range” of insulin settings that the recommendation engine can toggle between (i.e., “if my patients starts at a ratio of 1 U/10g carbs, recommendations can only go up to 1 U/5g carbs”), and “expert opinions” are used to prune out potentially erroneous recommendations. We’re curious to see how in-depth these “expert opinions” are and to what extent they regulate recommendations. Of note, the app’s final quality control measure is that patients have the option to accept or decline all recommendations, which Dr. Castle highlighted as an important safety feature.

  • Preliminary computer-simulated results (n=29) demonstrated promising improvements in TIR (70-180 mg/dl) and time <70 mg/dl – from 64% time-in-range at baseline to 83% by week 12! Wow! For the most part, the algorithm-generated recommendations matched physician recommendations, with a 56% overall agreement rate and a 3% overall disagreement rate (we’re not sure why they don’t sum to 100% - ostensibly the other 41% is a mix of agreement and disagreement). Although in-silico results must be interpreted cautiously and development is still early, reaching 70%+ time-in-range (to say nothing of over 80%, along with less than 1% below 70 mg/dL) with a smart pen decision support app is very promising! We’re eager to see how the app will compare to pump-based closed loop systems, as well as what the commercialization plan is – would Dexcom buy this, adding to its TypeZero portfolio? Dr. Castle emphasized that DailyDose is meant to take the place of an existing CGM app, so that users are not obligated to use multiple apps; we’re curious to see how comfortable users will feel relying on AI-generated dosing recommendations.

 

Baseline

Week 4

Week 12

Time-in-range

64%

74% (p<0.001)

83% (p<0.001)

Time <70 mg/dl

1.6%

0.8% (p<0.001)

0.8% (p<0.001)

  • Moving forward, Dr. Castle shared plans for an upcoming DailyDose pilot study in adults with type 1 diabetes. A total of 20 adults on MDI with an A1c ≥7.0% will be studied over the course of 9.5 weeks. Study participants will be given a Dexcom G6 and InPen for ten days of “usual care,” followed by 8-weeks using DailyDose. Time in Range, the primary outcome, from the ten-day run-in period will be compared to the last ten days of use.

  • Elsewhere on the decision support front, DreaMed’s provider-facing Advisor Pro is FDA cleared to provide pump setting recommendations (basal rate, insulin:carb ratio, correction factor) based on BGM or CGM data. According to our interview with DreaMed CEO Eran Atlas, a pilot for Advisor Pro in MDI has likely already commenced and support for type 1 MDI users is targeted for 2020. Dexcom also owns TypeZero’s MDI decision support software, which has done a study at UVA; we’re not sure when final outcomes will be presented, though preliminary outcomes from ATTD 2019 were mixed.

6. Sansum’s Dr. David Kerr: Smart Pens Have the Biggest Potential to Improve Outcomes (Outside of CGMs), But May Affect Clinician/Patient Dynamics

Sansum Diabetes’ Dr. David Kerr presented an optimistic overview of where he thinks smart pens will best fit into the current diabetes ecosystem, calling the device a “potential technology that [he] think[s] will be disruptive.” Other than with CGM, Dr. Kerr believes that insulin pens specifically have the most potential to improve outcomes by addressing insulin omission, which he categorized as (i) not giving any insulin or (ii) giving a dose of insulin that is not necessarily safe in amount or timing. Indeed, a study from March found that 36% of basal doses and 24% of fast-acting doses were missed or forgotten by people with diabetes. He noted that for clinicians in particular, not knowing how much insulin a patient has been taking makes it difficult to have meaningful dialogues about treatment, and this problem is especially prevalent in patients using MDI instead of pump therapy. Uniquely, smart pens can now allow patients and practitioners to “get a sense” of insulin omission. 

  • Interestingly, Dr. Kerr highlighted strain on the clinician/patient relationship as one of the potential downsides to using smart pens. Considering that diabetes can be a “difficult and miserable” condition to live with on a day-to-day basis, Dr. Kerr explained that enabling doctors to see how well a patient is taking insulin, or omitting it, can potentially complicate provider dynamics, especially for doctors in the primary care setting who may have less experience with patients with diabetes.

  • Dr. Kerr also introduced a new acronym T2iD or “Transitory Technology for Insulin Delivery.” He noted that with the influx of smart pens, technology might start to be used more intermittently, and patients might move between multiple devices based on their day-to-day needs. Dr. Kerr further surmised that smart pens might seriously impact the pump market. We believe the evolution of smart pens is so early that this is hard to call. On one hand, the rate at which pump-based AID is improving is radically faster than the smart pen field is currently moving; on the other hand, a compelling smart pen, CGM, and titration app could theoretically offer high time-in-range at a much lower cost.

  • Overall, Dr. Kerr seemed bullish on the future of smart pens, calling it a “very hopeful time for this technology.” Looking at his Roadmap to Smart Insulin Pens, Dr. Kerr pronounced that products in the “blue area” – referring to late-stage smart pens with dose calculators or advanced decision support – are starting to appear on the  market. Interestingly, we’re seeing a wide variety of players entering into the smart pen arena, from first-to-market Companion Medical’s InPen to big name contenders like Novo Nordisk (see above), Lilly, and Sanofi.

  • Dr. Kerr prefaced his talk with a firm reprimand to the overall diabetes community regarding lack of high-quality guidance, particularly when it comes to insulin. Despite insulin being a “very tricky and dangerous” treatment, the community often asks patients and clinicians to make important decisions in the absence of basic information: how much insulin to give and when. Citing an August 2019 paper in JAMA entitled “Evolution of the Cascade of Diabetes Care in the United States, 2005-2016,” Dr. Kerr noted that meaningful outcomes for patients with diabetes are not improving, especially for young, female, and non-white adults. (And, actually, especially for everyone, according to the 2019 Diabetes Atlas, just out today – see our update here.)

 

--by Rhea Teng, Albert Cai, and Kelly Close