February 15-18, 2017; Paris, France; Days #3-4 Highlights – Draft

*Results for these participants were only shown for the run-in and at one year, not for the three-month study phase. In looking at the pivotal data for all participants at all centers (see ADA 2016), these one-year results look very similar – suggesting the benefits were largely maintained.

4. International Diabetes Closed Loop Training Protocol Data, Main Phase to Begin Soon and Support Tandem/TypeZero PMA

Dr. Boris Kovatchev gave a progress report on the International Diabetes Closed Loop trial (to serve as Tandem/TypeZero’s pivotal), including first results from the 14-day training protocol phase and a picture of the integrated Tandem system. In 20 individuals thus far, the training protocol has seen similar outcomes to prior studies: an overall mean glucose of 156 mg/dl (148 mg/dl overnight), just 1.6% of the time <70 mg/dl (0.5% overnight), and 70% of the time in 70-180 mg/dl (79% overnight). The main phase of the trial (CT.gov posting here) will begin soon, randomizing 240 patients in a 2:1 ratio of closed-loop control vs. sensor-augmented pump therapy over six months. Notably, the FDA IDE approval actually includes a line that this can serve as a pivotal study to support a PMA, assuming the trial goes well and no safety issues arise. This is great assurance for Tandem/TypeZero and NIH. Dr. Kovatchev confirmed that the current system uses either a Tandem or Roche pump, Dexcom G5, and an Android smartphone running the inControl AP algorithm, with a planned upgrade in 6-8 months (3Q17) to add a Tandem t:slim X2 with the embedded TypeZero algorithm and Dexcom G6 sensor. We saw the first picture of the latter (see below), which utilizes a similar interface to the t:slim X2 with PLGS, includes new activity settings for “sleep” and “exercise,” and will be indicated for ages six years and up. The slide noted that upon approval, the product will be available as a software upgrade for all existing t:slim X2 users – a very compelling feature that we hope all pumps move to. We’ll expect more updates in Tandem’s upcoming 4Q16 call. 

5. Buckingham Sums up Closed Loop Landscape – “Night is the Low-Hanging Fruit”

Dr. Buckingham wrapped up a Novo Nordisk-sponsored symposium with a birds-eye view of the closed loop landscape: “Night is the low-hanging fruit for hybrid closed loop – there’s no major disturbance with food and exercise. Every hybrid closed loop system has done that quite well, reducing highs, reducing lows, and reducing variability.” The next major decrease in diabetes burden, he continued, will be with more fully closed-loop systems, noting that systems will not be perfect, but they only need to be good enough. He said that one of the keys to fully closing the loop is – as expected in a Novo Nordisk symposium – achieving a more rapid onset of insulin action, either via faster-acting formulations, faster delivery speeds, infusing over a broader sub-cutaneous space (e.g., perhaps with Unomedical’s Lantern or Capillary Biomedical’s catheter), or the use of adjunctive therapies. He provided brief commentary on five of the prominent closed-loop players (see below), hoped that a trial of faster-acting insulin aspart in closed loop is being planned (will algorithms need adjustment?), and remarked on the progress in the field over the last ten years: “This is really a new day. It’s a storied time we’re in here. I think the first ATTD meeting had 75 people, all engineers, and now we’re talking about human factors.”

• TypeZero (“I’m excited to see where this goes in the next year”);
• Beta Bionics (“This has done very well, and a lot of people like the qualitative meal announcement”);
• Bigfoot (“Bigfoot has been stalking around ATTD, I’ve seen them. They don’t have any data, but they’re moving forward”);
• Insulet (“What’s interesting is that the Dexcom CGM will talk directly to the disposable OmniPod pump, and the closed loop software will be right there in the pump. I just gave a talk on a feasibility study of the system this morning – post-breakfast glucose is a little high, but glycemic variability is significantly decreased”); and
• Medtronic (“Nighttime control is really good. Parents don’t have to get up, same for kids. Nighttime has been hugely different and vastly improved. During the day, kids are still counting carbs, bolusing – the work during the day is roughly the same”). This last point will be interesting to watch as Medtronic brings the 670G to market this Spring – people expecting to not have to think about their diabetes while on the system may be disappointed, unless they are eating very few carbohydrates (in which case, basal-only modulating can cope with meals without announcement). Expectation management will be key here, though hopefully Medtronic learned from the 530G launch.

6. First MiniMed 690G vs. 670G Feasibility Data: Adding Auto-Correction Bolus Improves Post-Meal Control

Dr. Thomas Danne shared the first clinical feasibility data (a small study, n=7) on the next-gen MiniMed 690G, adding DreaMed’s fuzzy logic algorithm to give automatic bolus corrections on top of the 670G. The 36-hour inpatient crossover trial compared the 670G and 690G and included five meals (one unannounced, one with a 70% bolus, and three with a full bolus), one snack, and one exercise session. Dr. Danne only showed glucose outcomes for the 690G: 71% time in 70-180 mg/dl (47% time in the tighter 70-140 mg/dl), 1.6% time <70 mg/dl, and a mean glucose of 153 mg/dl. These overall data were not compared to the 670G in this study, so it’s hard to know how much the 690G added. However, Dr. Danne did show one compelling example of an unannounced meal on the 670G vs. 690G, showing how the automatic correction boluses halved the time in hyperglycemia and shrunk the AUC (picture below). He concluded that the MD Logic Bolus in the 690G algorithm is “promising” and will be further studied in a recently NIH-funded trial starting later this year. Medtronic has not shared official timing on when this product might come to market. [Editor’s Note: Though Dr. Danne used “690G", Medtronic subsequently informed us that this product is now referred to as the “Advanced Hybrid Closed Loop System,” and not the MiniMed 690G.]

MiniMed 670G (right) vs. MiniMed 690G (left) with an unannounced meal in one participant

7. Additional MiniMed 670G Pivotal Data Published in DT&T, Sharing more CGM Results; “Generalizability” Noted as a Limitation

More MiniMed 670G three-month pivotal data was recently published in DT&T (Garg et al.) and mentioned a few times today, following the ADA 2016 poster, EASD 2016 oral, and two-page JAMA Research Letter. The paper is very data heavy and mostly adds more granular CGM data, broken up between adults and adolescents. Generally speaking, the results are very similar to the overall data we’ve previously seen – a good sign the device offered benefits in both groups, especially overnight. The benefits in adolescents after breakfast were also very striking, shown quite clearly in the paper’s glucose profiles (first shown at ADA).

• One of the most important statements in the DT&T paper comes on the last page: “...the generalizability of our results may be limited, given the lower baseline HbA1c levels for both cohorts relative to T1D exchange mean HbA1c levels; the frequent contact that study subjects had with site personnel; the fact that approximately half of the adolescents and two-thirds of the adults were using CGM at baseline; and the exclusion of subjects with HbA1c levels >10%, >2 recent episodes of severe hypoglycemia, and those with any recent episodes of diabetic ketoacidosis.”
  
  • This question of generalizability raises many questions as the 670G rolls onto the market this Spring in the US: What will the real-world experience be like? What users will like the system the most? What users may be disappointed or overwhelmed? Will the average HCP be able to prescribe the MiniMed 670G? Will payers cover the 670G, and if so, for whom? Will certain populations be excluded? How will patients use the system during the day vs. night? Will those eating fewer carbohydrates like automated insulin delivery more than high-carb users? (In Adam’s experience, auto-basal modulation + low-carb diet = fully automated insulin delivery without meal announcement.) On the other hand, will those who are less attentive to their diabetes like the 670G more?

8. 12 Weeks of Closed Loop with Zone MPC Adaptation: 0.3% A1c Reduction (Baseline: 7.0%), >60% Reduction in Hypoglycemia

Harvard’s Dr. Frank Doyle shared data from a 12-week home study of closed-loop control (n=30) using a Zone MPC algorithm with adaptation (adjusting carb ratios and weekly basal rates), Dexcom’s G4, a Roche pump, and a smartphone running UVA’s DiAs platform. The trial met its primary endpoint, showing a 0.3% reduction in A1c at 12 weeks from a very low baseline of 7.0% (p<0.005). Interestingly, mean glucose increased (142 to 151 mg/dl; p<0.005), though, notably, time <70 mg/dl declined by more than 60% (5% to 1.9%; p<0.005) – part of the lesser time in hypoglycemia would, of course, drive average mean glucose up. As such, the “quality” of mean glucose would have risen, given lower hypoglycemia. Time in 70-180 mg/dl did not change significantly (~73%), while time >180 mg/dl increased very slightly (21% to 25%; p=0.06). The study had three cycles of four-week parameter adaptation, with carb ratio chanced once per cycle and basal insulin changed four times per cycle (weekly), and Dr. Doyle emphasized that the first cycle did most of the settings adjustment for the carb ratio. Dr. Yogish Kudva noted in Q&A that during the course of the study, 358 parameter adaptation recommendations were made by the algorithm, and the clinical team accepted 323 (an impressive 90%). We’re glad to see more discussion and testing of adaptive algorithms, since this has potential to further improve closed loop glycemic control further without needing new devices or drugs.

9. Bionic Pancreas Bihormonal Pivotal Design: n=480, Superiority Design for A1c and Time <60 mg/dl in three age groups

MGH’s Dr. Steven Russell shared more details on the NIH-Funded Bionic Pancreas bihormonal Pivotal Study, expected to start in mid-2018 and complete in roughly mid/late-2019. The trial will randomize 480 patients in three age groups (pre-adolescent, adolescent, adult) to the bionic pancreas (n=320) or usual care (n=160) – much larger than the adult-only (n=312) design we expected following the NIH announcement earlier this month. (Dr. Damiano confirmed with us that NIH has only funded the adult portion of the pivotal, but additional funding will be sought for the pediatric cohorts.) Notably, the trial will be powered for superiority to show both a change in A1c from baseline (decrease of 0.5%) and time <60 mg/dl (reduction of 60%) – wow is this team ambitious. At least 1/3 of subjects will be pumpers and at least 1/3 will be MDIs. A PMA submission is expected after the six-month RCT, while a continued access study (n=107) will ensure there are 12 months of continuous exposure to glucagon (PMA supplement). An incentive study will allow the usual care cohort to continue on and use the Bionic Pancreas. The study is expected at 16 centers all across the US, including MGH (Dr. Russell), Stanford (Dr. Buckingham), UNC (Dr. Buse), University of Washington (Dr. Hirsch), Washington University in St. Louis (Dr. McGill), UCSD (Drs. Henry, Edelman, Pettus), Cleveland Clinic (Dr. Hatipolglu), and Henry Ford Medical Center (Ms. Kruger).

• As we noted earlier this month (following Novo Nordisk’s $5 million investment), Beta Bionics plans to submit IDEs for insulin-only and bihormonal iLet bridging studies by the end of May, start the studies by mid-July, and run them into September. The bihormonal bridging study will likely provide eight weeks of drug exposure to glucagon (presumably Zealand). The six-month insulin-only pivotal trial is expected to start by the end of 2017 or early 2018.

New Care Models, Dose Advisors, Delivery Devices, and Startup Highlights

10. Medtronic’s Turning Point Program: 2% A1c Reduction (10.1% Baseline) in initial Pilot; Includes Bluetooth BGM, Health COach

Medtronic presented notable data on its “Turning Point Program” in a poster, demonstrating a mean 2% A1c reduction from a 10.1% baseline in a 50-patient pilot over five months (n=35 completers) in partnership with Methodist Health Ministries. Turning Point uses a Bluetooth-enabled BGM, a patient mobile app, a one-on-one health coach, patient reminders (BG monitoring, medications, appointments), clinical decision support for PCPs, and as-needed iPro2 professional CGM to help patients with uncontrolled diabetes. Pilot participants had a mean age of 51, were 97% type 2, 75% on insulin, and 100% Hispanic. Notably, 83% of patients experienced an improvement in A1c, 80% of patients viewed educational material, and mean BG frequency was only 1.7 checks per day – that suggests this is more about accountability to a coach, backend analytics, and education than driving intensive device usage. Program retention was 70% (strong considering the high baseline A1c’s), with an average of 3.4 weekly interactions per patient. This type 2-focused program falls in Medtronic’s Diabetes Service & Solutions segment, and we first heard an inkling of it at Medtronic’s 2016 Analyst Day (though not called by this name). Watch this very inspiring two-minute video and view the full poster here. We’re glad to see the focus on helping those most in need with hopefully lower cost interventions. Scalability is always a question with human coaches, though the program seems to be backed by serious analytics capacity. According to Medtronic’s F3Q17 slide deck, the Turning Point integration with IBM Watson is “now live,” adding further predictive analytics (e.g., predicting risk of a hospital readmission). The poster concludes that Turning Point will expand to include other health metrics and greater population base. 

• “The Medtronic Turning Point program is intended to help patients with uncontrolled diabetes by facilitating patient engagement, remote monitoring and data-driven interventions. The pilot program, in partnership with Methodist Health Ministries (San Antonio, TX), utilized personalized coaching, technology and advanced analytics to engage patients, coordinate care, stratify risk and target resources while following the patient’s diabetes care plan and extending the physician’s reach outside the clinical setting.”

11. Glucommander Outpatient Maintains a 2.6% A1c drop over Six Months

For the second time this meeting (see first here), Dr. Bruce Bode presented data from Glytec’s Glucommander insulin management system – this time in the outpatient setting and demonstrating a sustained 2.6%  drop in A1c over a six-month period. Intermittent three-month data was presented in an ADA poster – from a high baseline A1c of 10.3%, patients ended three months with an estimated average A1c of 7.6% (p<0.000001). The study enrolled 42 type 1 and type 2 patients (one additional patient compared to the first three months). Impressively, patients were titrated to goal in 11 days. Over six months, A1c dropped from 10.2% to 7.6% (a “highly significant” 2.6% decline), and hypoglycemia was “extremely rare” – just 0.2% of blood glucose values were <54 mg/dl and 0.02% of values (just five instances) were <40 mg/dl. In a planned sub-analysis, all very engaged patients (those who input at least four blood glucoses/day) finished with A1cs below 7%. The total daily insulin dose increased slightly with Glucommander, though this increase was not significant. An impressive storyline from this study is time-savings – though unquantified, the small clinic staff (13 providers in total) was able to bring these poorly-controlled patients into range with minimal effort. Dr. Bode stated that “obviously this does work,” but unfortunately the weakness is that this is a non-randomized trial. Still, starting in the near future, over 10 hospital systems will launch the outpatient product. We believe insulin dose titration software, like Glucommander and many others, will be a major trend in the field over the next five years – better outcomes at lower costs in the toughest patients is a slam dunk. The real questions here lie with implementation, engagement, and business models: how will they be deployed (HCP-facing in an EMR, in a data platform like Glooko, on a patient’s phone like Voluntis), will HCPs and patients use them, and who will pay for them?

12. Interim Advise4U Study Results Show DreaMed’s AdvisorPro Pump Titration Software is Similar to Clinician Advice

Dr. Revital Nimri shared interim results from the MD-Logic Advise4U Pilot study of DreaMed’s AdvisorPro clinical decision support software to optimize insulin pump settings. Thus far, the hypothesis of non-inferiority has been validated: For six weeks, patients at Schneider Hospital assigned to either the Advisor (n=7) or the control group (expert physician-guided decisions; n=8) have spent similar time in range (52% in control vs. 50% with the Advisor), though the Advisor group spent slightly more time >180 mg/dl (42% control vs. 49% Advisor), and slightly less time <70 mg/dl (7% control vs. 2% Advisor). The clinicians and Advisor have used different methods to achieve similar outcomes, an interesting quirk of clinical decision support. Notably, the Advisor has made more adjustments, making 4.7 recommendations per patient while clinicians made 3.3 per patient. The Advisor also changes with more parameters than clinicians: The number of basal periods per day was not really changed by the physician, while the Advisor appears to increase the number of periods, moving toward less basal insulin in favor of boluses. Physicians didn’t adjust correction factors meaningfully, while the Advisor changed correction factor value by an average of ~30% during the day and ~50% at night (both in favor of higher insulin dose, in concert with lower basal doses). The Advisor also appears to suggest more periods for the insulin:carb ratio. The study will enroll an additional ~20 patients and is expected to wrap up in a year, and a multi-center, multi-national study with a similar design and funding from the Helmsley Charitable Trust is being planned now. The Advisor will eventually be incorporated into Glooko’s platform, pulling data directly from all the major pumps and making suggestions accordingly. 

• A small study detailed in a separate talk showed that within a practice, physicians only agree on ~40% of insulin titration decisions. This number is astoundingly low, and makes the case for a software-based algorithm like AdvisorPro that can take some bias out of the process and add highly objective data analysis. We see extremely high potential here to save providers time and drive to more nuanced insulin recommendations.
• It is interesting to see similar outcomes given different dose titration strategies. The Advisor pulls a number of levers, while providers tend to isolate variables (or be biased in favor of changing some over others) so as to reduce the degrees of freedom associated with a complex decision. We also noticed this earlier in the week in Medtronic’s Professional CGM session – an audience rarely agrees on what insulin dose changes will fix the problem, often because the problems are numerous and the eye is drawn to outliers. Might the Advisor’s intricate strategy show superiority over longer periods of time in less experienced clinicians? We think so.

13. Sensulin (glucose-responsive insulin) and Cam Med (flexible patch pump) Highlight ATTD’s First Startup Companies Session

In ATTD’s first-ever startup company presentation slot (nine companies), we were most impressed with Cam Med’s Evopump (“bandage-like patch pump”) and Sensulin’s work on glucose responsive insulin. We share details on these two early stage companies immediately below, followed by links to others that presented.

• Sensulin, founded by ex-Amylin scientists and investors, is developing a once-daily glucose-responsive insulin. A first-in-human trial is expected in 2018, and “big news” might come in about 30 days. The company hopes to validate its first clinical candidate this year. The liposome-based insulin uses recombinant human insulin and is glucose responsive via boronate linkers (Agglomerated Vesicle Technology, or AVT). The links cleave in response to glucose, thus regulating insulin release (Dasgupta et al., PLOS One 2012). The company has been working to reduce AUC for meal challenges, though the rat data looked encouraging for a once-daily insulin that covers basal and blunts some prandial excursions (picture below, though glucose still rose up to ~300 mg/dl). Avoidance of hypoglycemia looks very strong. At minimum, CEO Mike Moradi expects a “safer basal insulin” that can meet “some portion” of mealtime needs for many type 2s. For a subset of type 1s, he said, the insulin may alleviate the need for MDI. We’re glad to see the company is moving along, as we last recall hearing from Mr. Moradi at LyfeBulb’s 2015 Social Club event. Sensulin’s Chairman of the Board is Dan Bradbury (former Amylin CEO), and the Scientific Advisory Board includes past ADA president Dr. Alan Cherrington, Merck’s very impressive former Franchise Head of Diabetes and Obesity Dr. John Amatruda, CEO of Profil [now Prosciento] Dr. Marcus Hompesch, former Amylin CMO Dr. Orville Kolterman, and former JDRF CEO Dr. Alan Lewis.

• Cam Med has developed a very thin, flexible, flat patch pump (3 x 2 x 0.2 inches) that uses a unique reservoir array and electrolysis drive system. The three-day pump is disposable (300 units), uses a handheld controller, and is expected to have lower manufacturing cost and be capable of delivering multiple medications. Instead of a single reservoir, the Evopump uses many reservoirs arranged in an array – each reservoir is rigid, but the spaces between them are flexible, allowing the pump to bend (see picture below). Medication is delivered through each reservoir using electrolysis – the gas expansion pushes a membrane and moves the medication. Cam Med has seen ±2% accuracy 95% of the time from individual reservoirs, which it believes is more accurate than the current screw-driven pumps. The first mass producible prototype of the reservoir/pump array was just manufactured, and the company owns the IP on the elements that enable the thin, flexible design. Cam Med has won several competitions and secured $440,000 in non-dilutive funding so far; the plan is to partner with an incumbent for commercialization. Contact CEO Larry Alberts at larry.alberts@myevopump.com.

• Other presenting companies included:
  
  • Biomicro, a fully implantable CGM company. The device is expected to last six months, is about the size of a grain of rice, and is charged wirelessly via smart watch. Animal trials are expected this year. Contact: Nansheng.shen@biomicro.com.sg.
  • Jupiter Devices, a non-invasive glucose monitoring startup using RF in the microwave spectrum. The device is still in benchtop testing. Dr. Jessica Castle is an advisor.
  • Perikinetics (Thera Nova incubator), a fully implanted intraperitoneal artificial pancreas startup. The system includes both CGM and insulin delivery. Animal studies are planned in the upcoming year. Drs. Howard Zisser, Eric Renard, Frank Doyle, and Ananda Basu are advisors.
  • Ilya Pharma, who has a lactic acid bacteria-based wound healing product. A phase 1 clinical trial is expected this year. Contact: Evelina Vågesjö, CEO at evelinawagesjo@gmail.com.
  • Hci Viocare, a company developing smart insoles (FlexiSense). The device can detect pressure and shear forces in shoes (and other devices) and send the data to smart phones.
  • UND Life Sciences, developing a small lipid molecule for diabetic retinopathy. Preclinical studies are in progress, and the company hopes it can be delivered in drops instead of injections. Contact: undurti@hotmail.com.
  • Predictive Autoimmune Biomarkers, maker of PAB-ENDOSULIN, a biomarker predictive of loss of insulin prediction earlier than C-peptide.

14. CeQur PAQ Lowers A1c by 1.4% in Small Observational Study

Medical University of Graz’s Dr. Julia Mader presented new clinical data of the CeQur PAQ basal-bolus patch device in type 2 diabetes: In a single-center, observational study (n=17), A1c dropped 1.4% (baseline 8.5%; p<0.05) after 12 weeks on PAQ. This improvement came with little tradeoff, as there was no significant change in weight and zero severe hypoglycemia – by study’s end, most were sad when they had to give the PAQ device away and would’ve preferred to keep using it. In addition to A1c change, five of the patients were selected to wear CGM for the duration of the study and saw a highly significant (p<0.001) improvement in time in range after 8 weeks – increasing from 51% to 70% of time spent in 70-180 mg/dl. Notably, there was little to no hypoglycemia at either baseline or after eight weeks of PAQ, and postprandial spikes appear to have been attenuated by use of the device. For those participants not wearing CGM, every point in the seven-point SMBG profile was significantly reduced at 12 weeks vs. baseline, and mean blood glucose decreased from 181 to 161 mg/dl, and the time below 70 mg/dl was unchanged (we wonder if the regimen could’ve been even more aggressive). Dr. Mader emphasized the ease of therapeutic initiation, sharing that 80% of the participants remained on the first basal rate that was chosen, while two required one basal rate change and two required two basal rate changes. There was a slight increase in total daily insulin dose, but she explained this as a by-product of the trial’s treat-to-target design (and obviously high A1c). Patients’ overall treatment satisfaction score significantly improved, as they were particularly pleased with the flexibility and convenience of PAQ – commonly cited advantages of tubeless insulin delivery. Though small and observational, this study confirms that PAQ could be effective, especially in type 2s, and we hope this device move along to commercialization and manufacturing scale. We reported last April that PAQ was slated for a 2017 US launch, though Senior VP Mr. Jay Warner confirmed in late September that the company had not yet filed with the FDA (it was CE marked in 2012). There was no concrete update at ATTD, though Mr. Warner said that the company is making the “final iterations to make sure [it] can scale up to manufacture at volume and at an affordable price.” CeQur raised $100 million in Series C financing in September 2015 and announced a significant facility expansion last April.

15. CeQur Data Analysis Reveals Correlation Between A1c and Insulin Delivery in Type 2

A fascinating oral presentation from type 2 patch pump company CeQur, utilizing data from the dQ&A USA Patient Panel, showed a correlation between A1c and insulin delivery type, with more discreet, easier to use, and convenient insulin delivery (i.e., pens and pumps vs. syringes) associated with greater levels of glycemic control. In dQ&A Patient Panel responses from patients with type 2 diabetes using an insulin device (n=1,579, Q1 2016), a relationship exists between insulin delivery device and clinical outcome: pump users were less likely to have an A1c >9% (12%) than their counterparts using pen only (20%), syringe alone (26%), and syringe+pen (30%; p=0.033). CeQur’s Mr. Jay Warner (a study co-author) hypothesized that this is a matter of therapeutic visibility and convenience: pumps (and pens to a certain degree) are more discreet and convenient to use than syringes, perhaps promoting better therapeutic adherence. Pump use was also associated with another previously-determined predictor of clinical success: being married. Cost is yet another critical factor: Mr. Warner emphasized that pump use can be costly, and typically occurs in patients with better insurance and higher incomes. Mr. Warner framed this work in the context of the clear room for improvement in insulin delivery. He pointed out that, as of 2012, 29% of the US population was on insulin, nearly 69% of whom were not at target – sobering statistics that raise the question of which factors characterize those patients on insulin who are able to achieve their glycemic goal, and could be predictive of clinical success. There seems no question that better insulin delivery devices and better dosing guidance both have a role in getting more patients to goal.

Therapy Highlights

16. Toujeo vs. Tresiba: Head-to-Head PK/PD Data from an Eight-Day Euglycemic Clamp Study

Dr. Tim Bailey presented data from a Sanofi-sponsored head-to-head study of next-generation basal insulins Toujeo and Tresiba, which found that Toujeo results in 20% lower variability (i.e., a flatter PK/PD profile) vs. Tresiba when superimposing glucose infusion rate (GIR) curves for 0.4 u/kg daily doses – the treatment ratio was 0.8 in favor of Toujeo (p=0.047). Participants (n=48) were split into two cohorts, receiving either 0.4 u/kg/day (n=24) or 0.6 u/kg/day (n=24) of Sanofi’s Toujeo (insulin glargine U300) or Novo Nordisk’s Tresiba (insulin degludec U100). Each participant underwent two 30-hour clamps on day eight of each of two study periods. On days 1-7, they just took the basal insulin at 8 am (i.e., no clamp). After each phase, individuals entered a washout period before being switched to the other basal insulin treatment. This study design allowed for within-participant comparisons of the two products, and while there was no significant difference in primary endpoint between the 0.6 u/kg daily doses, Toujeo at 0.4 u/kg/day achieved a smoother GIR curve over 24 hours vs. Tresiba at 0.4 u/kg/day. Toujeo’s action was reported to achieve plateau-like insulin exposure between hour two and hour 16, followed by slight decline out to hour 30. Tresiba’s action was reported to increase from hour one to hour 10, when it reached peak and then declined out to hour 30 with little to no plateauing. The study also looked at six-hour insulin concentrations and glucodynamic activity as secondary endpoints: six-hour insulin concentrations were similar for both basals, but Toujeo showed a more even distribution of six-hour glucodynamic activity over 24 hours.

• Notably, this trial delivered basal insulin injections to all participants in the morning (8 am), pre-breakfast – timing that could possibly favor Toujeo over Tresiba. Toujeo hasn’t shown as flat a PK/PD profile over a full 24 hours compared to Tresiba in independent studies of each. Moreover, Tresiba benefits from a flexible dosing claim on its label, allowing patients to take their basal injection at different times on different days due to steadier-state action over a full 24 hours.
• Ultimately, Dr. Bailey acknowledged that a larger, longer-term trial is needed to determine the differential advantages and disadvantages of these next-gen basal insulins. We’re not sure if independent investment would be warranted in such a trial – both insulins are clearly better than the previous generation, and how they differ from each other is likely more about marketing than pressing clinical research questions. [On the other hand, we do think a study of basal dose timing – morning, midday, evening, bed – paired with dose titration software support would be very compelling.] The more important piece of this research is not pitting Toujeo and Tresiba against each other to determine a winner, but demonstrating that both of these next-gen products – “true” 24-hour insulins – are superior to the prior generation of basals, offering greater A1c-lowering and a better patient experience.

17. Novo Nordisk Symposium Highlights Fiasp for Use in Insulin Pumps, Long-Term Cost-Effectiveness

At a Novo Nordisk-sponsored symposium, Profil Institute’s Dr. Eric Zijlstra spoke to the significance of the company’s Fiasp (faster-acting insulin aspart) in the evolution of insulin therapy: The next-generation, ultra-fast insulin results in fewer, smaller postprandial glucose excursions and could be especially advantageous for pump users. He reviewed data from a clinical pharmacology study of Fiasp which found that the advanced agent works significantly faster than NovoLog (insulin aspart) – onset of exposure came 11.8 minutes faster, insulin exposure within the first 30 minutes was 3x higher, and insulin action within the first 30 minutes more than doubled. Fiasp achieves maximum concentration 25.7 minutes faster vs. NovoLog, and maximum action 18.7 minutes faster – that should have a very solid impact at mealtime, given the importance and challenge of pre-bolusing. Importantly, offset of Fiasp also occurs 24 minutes faster vs. NovoLog, making for a more effective faster-in, faster-out bolus insulin. This will be particularly pertinent for use in insulin pumps, according to Dr. Zijlstra, as faster absorption of a bolus is a key next step for advancing the field – particularly with regards to closed loop therapy, which will almost certainly improve with Fiasp’s profile. Fiasp was EMA-approved in early January 2017 and a primary focus of Novo Nordisk’s ATTD exhibit hall presence (see below). The insulin still awaits US approval following an FDA Complete Response Letter issued last October; during Novo Nordisk’s 4Q16 update, we learned that the company plans to resubmit the drug to the FDA this quarter (1Q17), with hopes of approval by end of year.

• During Q&A at the end of the symposium, Dr. Vincent Woo (University of Manitoba, Winnipeg, Canada) argued for cost-effectiveness of Fiasp. He suggested that real-world data will reveal more dramatic A1c-lowering with Fiasp vs. NovoLog compared to clinical trial data. We agree with that. Studies thus far have used basal insulin optimization to clearly demonstrate the superior effects of Fiasp on postprandial glucose, and have shown slightly better A1c reductions with faster-acting vs. regular aspart. “In the real world, where basal insulin optimization doesn’t really exist, you might see even more of a difference,” Dr. Woo explained, adding that over time, a 0.1% or 0.2% greater lowering of A1c could meaningfully impact the incidence of diabetes complications. We wonder what payers would think of that argument. It’s also possible the real-world efficacy of Fiasp will be much better, but for a different reason: better mealtime control in those who do not take their insulin 20 minutes before eating, as would be done in a clinical trial. As with any new drug, insurance coverage will be a determining factor in the product’s commercial success (especially in the US, assuming FDA approval comes through by the end of 2017). Although the phase 3 clinical program for Fiasp has shown incremental rather than truly disruptive therapeutic benefits over NovoLog – especially compared to the improvement with next-generation basal insulins (Novo Nordisk’s Tresiba and Sanofi’s Toujeo) over earlier basal insulins (namely, Sanofi’s Lantus) – we still see value in Fiasp for a better bolusing experience and potentially very strong closed loop improvements.

18. Type 1 Diabetes Immunotherapy Panel Details Promising Early-Stage Research

ATTD drew to a close with a packed Saturday afternoon panel on the status of immunotherapies for type 1 diabetes. An all-star panel reviewed the current state of immunotherapy for type 1 diabetes treatment, and provided updates on some of the most cutting-edge research in this domain. Overall, we were struck by the number of moving pieces here –energy and creativity is required to exploit properties of the immune system to protect the beta cells, and the basic science experimentation and trials will still require a great deal of time.

• The great Dr. Chantal Mathieu (KU Leuven, Leuven, Belgium) discussed her cutting-edge work using the lactococcus lactis bacteria as a delivery system for therapeutic antigens. Typically used in dairy fermentation, the lactococcus lactis bacteria can be genetically engineered to synthesize and secrete proteins of interest – in the case of type 1 diabetes immunotherapy, antigens such as pro-insulin, IL-10, anti-CD3, and LL-PNS.  Impressively, Dr. Mathieu’s research group determined in mice that the lactococcus lactis-facilitated delivery of a specific set of three proteins (anti-CD3 + LL-PNS + IL-10) to mice newly diagnosed with type 1 diabetes caused diabetes reversal at a rate of almost 60% by 14 weeks. Dr. Mathieu’s current work focuses on identifying the differences between the “responder” mice who undergo diabetes remission with this therapy versus the “non-responders” who do not. Early evidence suggests that distinctions in the Foxp3 regulatory pathway in regulatory T cells may be responsible – an indication that these markers could potentially be used as the basis of personalized medicine approaches to identify patients with type 1 diabetes who are likely to respond to this kind of therapeutic strategy.
• Dr. Mark Peakman (King’s College, London, UK) discussed his novel peptide-based therapy for type 1 diabetes, a strategy involving the administration of antigens in order to reestablish or induce tolerance, much like a vaccine. After the success of Dr. Peakman’s phase 1 MonoPepT1De study demonstrating the ability of vaccination with the a peptide mimicking the C19-A3 region of proinsulin to reduce insulin dose and A1c and raise C-peptide levels in individuals with type 1 diabetes in their first 100 days of diagnosis, his research team decided to investigate the effectiveness of a cocktail of peptides targeting multiple areas of the beta cell. Accordingly, the so-called MultiPepT1De study (also phase 1) was launched in 2015 and is expected to complete sometime in 2017. Dr. Peakman shared that a follow-up phase 2 study will likely be initiated this year as well.
• “The artificial pancreas can’t be a cure, because the brain is not a pancreas. As we get closer and closer to closed loop, we need to simultaneously intensify our efforts to find a biological cure for type 1 diabetes.” University of Florida’s Dr. Desmond Schatz eloquently captured the importance of research in this field, despite the difficulty of slow-moving studies and tough risk:benefit balance in getting an effective immunotherapy to patients. We wonder if closed-loop devices may make this balance tougher, raising the safety/effectiveness bar for cure therapies further.

19. Annual ATTD Yearbook

The ATTD Yearbook covered all the progress made in 2015-2016 diabetes research spanning therapy and technology. Click here for the full Yearbook, published in Diabetes Technology & Therapeutics.

20. Exhibit Hall

We visited 12 booths at this year’s exhibit hall (cleverly-placed alongside frequent coffee and refreshments!) – Abbott, Ascensia, Dexcom, Glooko, J&J, Lilly, Medtronic, Novo Nordisk, Roche, Sanofi, Senseonics, and Ypsomed.

Exhibit Hall

Abbott

Abbott’s trademark vibrant yellow booth showed off the LibreLink and LibreLinkUp apps, real world data from FreeStyle Libre use (see day #1 for our analysis), and a video of Dr. Rich Bergenstal discussing the one-page AGP. We continue to look for standardization in how glucose is assessed and we really like ths one-pager – see below from Glooko about expanded use of AGP. Abbott's FreeStyle Libre consumer version hasn’t yet received FDA approval in the US – we learned on the 4Q16 call that the company hopes for a 2H17 launch and, notably, that Abbott has filed for both adjunctive and replacement label claims.

Ascensia

Ascensia exhibited the Contour Next Link 2.4 meter, which is available with Medtronic’s MiniMed 640G internationally and in the US with the 630G and upcoming 670G. The booth also showed off the Bluetooth-enabled Contour Next One meter and the Contour app virtual-reality style (we previously saw the demo at EASD). The Contour Next One meter is now available in at least 14 European markets, with a US launch expected early this year. The motif of the booth was “illumination” – “Seeing how everyday activities affect blood glucose – that’s illuminating”; “Their diabetes. Illuminated”; “Tap screen to be illuminated” – likely a reflection of the SmartLIGHT feature on the Next One meter that indicates in-range (green), low (red), and high (yellow) results. All the meter companies seem to have this now, and we wonder if patients find it useful and meaningful. Some, we imagine, may find it annoying to have a colored light reminding them they are high or low. Others may love it, perhaps because they don’t remember what one’s blood glucose should be. We wonder if simple dosing guidance for type 2s could follow from this: if the light is orange, take X units, if the light is green, take Y units. We do really believe that this clinical reminder could help patients and could be a "nudge" toward better care if presented optimally.

Dexcom

Dexcom’s booth had a wide countertop showing off the newly launched Android G5 app on smartphones, our first in-person look. The new G5 app launched in the UK, Ireland, Netherlands, Germany, and South Africa last month, and our first demo showed a pretty identical user experience to the Apple iOS version. The booth also shared Dexcom’s recent publication wins, including reprints of the DIaMonD type 1 results (CGM in MDI) published in JAMA last month. The now-trademarked tagline, “CGM First,” adorned the back wall of the booth, emphasizing Dexcom’s goal to drive CGM use before pumps. Indeed, for years, Dexcom's customers were pump-users – that has now fallen to about 30%, given the rise in those on MDI who have started CGM. CGM reimbursement has improved in the EU and we're eager to see how Dexcom's business progresses there.

Glooko

The big news in Glooko’s booth was the launch of its new mobile app on Apple and Android, which finally rolled out last week. This adds some nice pattern recognition features: (i) the time of day when BG levels run high or low; (ii) how current BG levels compare to other time periods; and (iii) the day of the week with the best BG control. We like the work to incorporate emojis and make Glooko feel friendlier and less clinical, more like a "friend." The new mobile app also includes an Ambulatory Glucose Profile – it is tremendous news to see this CGM data display expanding. The rep said the goal is make Glooko less of a retrospective app and more of a daily diabetes companion app – no surprise given the expanding work on insulin dosing decision support, including the new partnership with Novo Nordisk. Glooko has always had a strong mobile offering and we’re glad to see the combined efforts with diasend to drive even better use of diabetes data globally. Diasend’s in-clinic transmitter was in the booth, and we assume a combined product will still roll out this year (see our coverage of the merger from last fall – this is exciting!).

J&J

J&J made news late last month when it announced that it will “explore strategic options” for its Diabetes Care segment (LifeScan, Animas, Calibra), including operating partnerships, joint ventures, strategic alliances, or a sale of the businesses. For the small booth at ATTD, however, it was business as usual – the Animas Vibe insulin pump, the Bluetooth-enabled Verio Flex BGM, and infusion sets were displayed and detailed by reps. The cadence of new products has obviously slowed in the past few years – the Vibe was CE Marked nearly six years ago! We would love to see the Calibra as we have high hopes for this product that has big potential to make mealtime insulin dosing so much more flexible and discreet.

Lilly

Lilly occupied a small, unassuming side booth, displaying samples of the GLP-1 agonist Trulicity pen, the Humalog insulin KwikPen, and the Abasaglar KwikPen (recently made available in the US under brand name Basaglar). Although the booth was small, it was terrific to see support from all the major insulin companies at this meeting.

Medtronic

Similar to EASD, Medtronic demoed the Guardian Connect standalone mobile CGM in its booth. The iOS app looks spiffy and we appreciated the meal and exercise markers, which look far better than those in the Dexcom G5 app. The rep told us the device is now in 15 EU countries and will “soon” enter Chile; in Medtronic’s earnings presentation this week, these were characterized as “pilot launches in major European markets” with a “positive response.” Guardian Connect remains under FDA review (with the new Enlite 3 sensor) and FDA approval is expected in roughly April/May. Otherwise, the MiniMed 640G and iPro2 professional CGM with Pattern Snapshot were on display; we still have yet to see the MiniMed 670G hybrid closed loop in an international exhibit hall. As of JPM, the 670G was expected to launch outside the US in May-October of this year.

Novo Nordisk

Novo Nordisk boasted a midsize to large booth at the center of the long exhibit hall, dedicated entirely to its very recently (January 2017) EMA-approved faster-acting insulin aspart, Fiasp. Against a crisp, white backdrop, the booth’s signage emphasized the drug’s rapid action profile: the main wall depicted a lunch with orange juice, an apple, and a sandwich overlaid with text to suggest that Fiasp begins working “from the first bite.” This motif was continued throughout the rest of the booth, with images of apples inlaid with a stopwatch on the back walls, and a bowl of apples on the booth’s central table – making it a very popular stopping place for attendees during conference breaks. A team of Novo Nordisk representatives dressed in yellow stood on the outskirts of the booth, offering helpful demos of the Fiasp FlexTouch pen and guiding conference attendees through Fiasp’s clinical data on interactive iPad displays. Feedback appeared largely positive and we look forward to seeing how Fiasp performs in EU markets. After receiving a very unexpected Complete Response Letter (CRL) in October 2016, Fiasp will be imminently resubmitted to FDA under a class II resubmission, with US approval expected by the end of 2017. It is said to be incrementally better – not a breakthrough in itself, but ideally it will lead to one. In the meantime, we believe many people with diabetes who can access Fiasp would certainly take the "better," given how hard diabetes is to manage.

Roche

At Roche’s exhibit, we got to handle the Accu-Chek Insight CGM for the first time (compare size to US currency below), learned that next-gen Accu-Chek Guide BGM will launch in Germany, Italy, and the US in 1Q17 (already in Australia, Switzerland, and Denmark), and that the Accu-Chek Instant BGM (streamlined feature set including a target range indicator [fantastic!], Bluetooth connectivity, and just a single button) will launch this month in Europe, on the earlier side of “2017” expectations in the 4Q16 update. A rep told us that the Instant may be better for patients who don’t need all of the whistles and bells offered by the Guide, but just a quick indication of blood sugar. The mySugr integration partnership was advertised in Roche’s corporate symposium with promises of “more to come,” but the just-signed exclusive deal with Medtronic to provide Bluetooth-enabled BGM for future Bluetooth-enabled Medtronic pumps wasn’t discussed at all at the conference – no surprise given that this is probably multiple years away. Also displayed were the DiaPort injection port with internal tubing and the SmartPix data display/analysis software. 

Sanofi

Sanofi’s ATTD exhibit hall presence largely matched what we saw last year, with emphasis on first-in-class MyStar DoseCoach BGM. Sales reps highlighted the integration of insulin glargine titration support (for next-generation basal insulin Toujeo) with BGM, and the download option to MyStar Connect, a management software platform that collects a patient’s MyStar DoseCoach data and presents it in one comprehensive package to HCPs. When is this coming to the US?! For the first time we can recall, we noticed AgaMatrix’s new Jazz 2 Wireless BGM (Bluetooth-enabled) on display, meaning Sanofi is also now distributing it under the MyStar brand – this is great to see, given the huge value of connectivity and the hardware challenges with iBGStar. Sanofi also promoted new-to-market basal insulin/GLP-1 combination Suliqua (branded Soliqua in the US) on the outer walls of the booth. Messaging highlighted (i) how the fixed-ratio combo of insulin glargine/lixisenatide improves both fasting and postprandial glucose; (ii) how the drug “helps more patients put high percentages behind them" – a very appealing message backed by strong data; and (iii) how the availability of two SoloStar pens for Suliqua in Europe offers greater dosing flexibility, an advantage over Novo Nordisk’s Xultophy (insulin degludec/liraglutide). As a reminder, the FDA only approved one SoloStar pen for Soliqua in the US (due to potential "confusion" on the part of patients and HCPs, which was surprising given all the complexity patients on MDI move through daily).

Senseonics

Just three meters from the Roche booth sat the bustling Senseonics booth, where we walked by as Dr. Mark Christiansen was presenting results from the PRECISE II US pivotal trial of the implantable Eversense CGM system (first seen at DTM; MARD=8.8% vs. YSI) to a large crowd. A rep told us that Senseonics is hoping to get CE marking for the new Eversense app (featuring Android, iOS, and Apple Watch compatibility, remote monitoring by up to five people, and a new fan-favorite “temp profile,” allowing 36-hour changes in alarm threshold), 180-day indication, and 55% smaller transmitter any day now. We were happy to hear that the company will be offering free transmitter upgrades to patients upon approval. We also learned that, in addition to deals with Rubin Medical (a very strong distrubutor) and Roche, Senseonics has had a small distribution agreement with Pharmanova in Finland “for the past few months” – the company plans to distribute in the US itself once the system is approved by FDA (filed in late October; launch expected in 2H17). A rep shared that clinicians at ATTD are beginning to picture their patients using the implantable CGM “because of the questions they were asking” about insertion/extraction procedures and patient satisfaction.

Ypsomed

Ypsomed’s YpsoPump was on display in its expansive booth, and we confirmed with reps that it has launched in the UK, Netherlands, and Germany. The rep said initial feedback has been very positive on the fully icon-based touchscreen interface and prefilled insulin cartridges (Novo Nordisk PumpCart). The manual fill option is hopefully expected this year, on par with the timing shared in the company’s November update, for those who want to use other insulin. The rep did not comment on whether the pump has also launched in Czechia (Czech Republic), as was expected in last fall’s update. In our demo of the pump, we noticed it infuses bolus insulin very fast (like the Animas One Touch Ping/Vibe), though the scrolling to select a bolus size is very slow (a limitation of the icon-based interface). All eyes will be on Ypsomed’s spring update as it will share the first details on this launch alongside continued OmniPod distribution – how will the products co-exist?

-- by Adam Brown, Abigail Dove, Brian Levine, Payal Marathe, and Kelly Close