June 7-11, 2019; San Francisco, CA; Day #5 Highlights – Draft

ADA 2019 is, as we say, in the books, and this final highlights report is not to be missed – with a full CVOT readout (PIONEER 6 for oral semaglutide) and new renal analyses from CARMELINA (for DPP-4 Tradjenta) and CREDENCE (for SGLT-2 Invokana), day 5 offered plenty to be excited about. Read on below – and stay tuned for more ADA coverage in our full report!

Diabetes Therapy Highlights

1. PIONEER 6 Identifies Non-Significant 21% RRR on Three-Point MACE with Only 137 Events; 1% A1c Drop + ~9.3 lbs Weight Loss After 1.3 Years; PIONEER + SUSTAIN Pooled Data Support Semaglutide’s MACE Benefit

The final session of ADA 2019 featured results from the PIONEER 6 CVOT (n=3,183, median follow-up 16 months) for Novo Nordisk’s phase 3 oral semaglutide, building on topline results released last November (see the slides here): While oral semaglutide did not demonstrate superiority vs. placebo on the primary outcome of three-point MACE, a non-significant 21% relative risk reduction was observed (hazard ratio 0.79, 95% CI: 0.57-1.11, p<0.001 for non-inferiority, p=0.17 for superiority). See the full results in NEJM. Toronto General Hospital Research Institute’s Dr. Mansoor Husain detailed the cardiovascular outcomes, including impressive Kaplan-Meier curves for all-cause mortality and CV death (see below). A 49% risk reduction was found with oral semaglutide on the former (HR=0.51, 95% CI: 0.31-0.84), and a 51% risk reduction was found on the latter (HR=0.49, 95% CI: 0.27-0.92), which drove the non-significant trend in favor of oral semaglutide on three-point MACE. On the other components, there were more non-fatal MI in the oral semaglutide arm (HR=1.18, 95% CI: 0.73-1.90), but fewer non-fatal strokes (HR=0.74, 95% CI: 0.35-1.57). However, these secondary endpoints were not-significant.  Considering that the trial was powered only for safety, meaning the total number of events was much lower than other CVOTs, its results should be interpreted with caution. On balance, this low number of events also makes the significant reductions in mortality somewhat difficult to interpret. On all-cause mortality, ~two-thirds of events were CV-related, and equal reductions were seen in both CV and non-CV death. Importantly, expanded CV outcomes revealed no safety signals on hospitalizations for heart failure or unstable angina. Three-point MACE estimates were consistent across subgroups, suggesting the primary endpoint results to be consistent across the enrolled population.

• As a reminder, oral semaglutide has been submitted to FDA with a priority review voucher, meaning a decision is expected by September 2019. Novo Nordisk has also requested CV indications for both oral semaglutide and Ozempic (injectable semaglutide), based on PIONEER 6 and SUSTAIN 6, and decisions on both are expected ~January 2020. Submission in Europe and Canada is also complete.

• Metabolic and safety outcomes. Dr. Ofri Mosenzon shared metabolic and safety outcomes: Oral semaglutide significantly reduced A1c (-1.0% vs. 0.3%) and body weight (-4.2 kg weight loss vs. 0.8 kg weight gain) vs. placebo, from baselines of 8.2% and 90.9 kg, respectively – very strong results after a median 16 month of follow-up. Very notably, both of these come despite significantly more initiation of other antihyperglycemic agents, including SGLT-2 inhibitors, in the placebo arm (see below). Of course, it’s entirely possible that these reductions may have contributed to the CV safety and efficacy observed with oral semaglutide, though results from other GLP-1 CVOTs achieved smaller treatment differences and still reduced CV risk. However, it’s worth noting that nearly the exact same reductions were seen with the higher dose of injectable semaglutide in SUSTAIN-6 – 1.05% A1c drop and 4.35 kg weight loss (both placebo-adjusted). Dr. Mosenzon also highlighted a modest but significant reduction in systolic blood pressure with oral semaglutide (-5 mmHg vs. -2 mmHg), despite more antihypertensives and diuretics being initiated after baseline in the placebo arm (see below). On safety, oral semaglutide conferred an elevated number of gastrointestinal events (108 vs. 26), consistent with the GLP-1 class, but there were no other imbalances. There was a modest increase in diabetic retinopathy with oral semaglutide vs. placebo (7.1% of patients vs. 6.3%), but this was not significant. Importantly, Dr. Vivian Fonseca noted in his independent commentary that diabetic retinopathy at baseline was excluded from the trial – a population that had an increased risk of retinopathy complications in SUSTAIN-6 and a population that we’re disappointed to see left out though it makes sense from a risk/benefit perspective.

• Trial design and baseline characteristics. Dr. Stephen Bain presented trial design and baseline characteristics. PIONEER 6 was an international trial, enrolling participants from 21 countries. Around half were from North and South America, one-third from Europe, and the remaining from Africa and Asia. Participants were randomized to either 14 mg oral semaglutide or placebo. Key inclusion criteria for those with type 2 diabetes included either being over 50 years and having established CVD or moderate CKD (this ended up being ~85% of trial participants), or being over 60 years and having CV risk factors (~15% of trial participants). Notable key exclusion criteria included recent treatment with a GLP-1 or DPP-4 and having proliferative retinopathy (in light of the retinopathy signal seen in SUSTAIN-6, which did enroll this patient group). In total, 3,183 patients were randomized in the trial, with a high 99.7% trial completion percentage – Dr. Bain highlighted this achievement as a testament to the commitment of the trial participants and the study investigators. In terms of glucose-lowering agents used at baseline, 77% were on metformin, 60% on insulin, 32% on a sulfonylurea, 9% on an SGLT-2 inhibitor, and 4% on a TZD.

• Summary. Session chair Dr. John Buse presented a post hoc analysis combining the data from PIONEER 6 and the SUSTAIN 6 CVOT for Ozempic (injectable semaglutide), showing a significant 24% RRR on three-point MACE (95% CI: 0.62-0.92) and a 35% RRR on stroke (95% CI: 0.43-0.97) – see full results below. While there was no significant risk reduction on CV death or non-fatal MI, both trend in favor of the semaglutide molecule. Our sense is this pooled analysis may play into FDA’s review of Novo Nordisk’s requested CV indications for both oral and injectable semaglutide. Additionally, Dr. Buse reviewed the totality of primary endpoint results from GLP-1 and SGLT-2 CVOTs, pointing to consistently positive effects on three-point MACE with all long-acting GLP-1s (only ELIXA for lixisenatide did not demonstrate superiority or trend strongly in favor of the GLP-1). Dr. Buse concluded his talk by expressing hope that eliminating the injection barrier with GLP-1s will lead to more widespread use, characterizing oral semaglutide as a great addition to this new and exciting era of diabetes management.

• Independent commentary. In delivering the independent commentary, Dr. Vivian Fonseca expressed great excitement over the clinical potential of oral semaglutide – it turns out that there are a low number of events and some differences between PIONEER 6 and SUSTAIN 6. While effects on three-point MACE and stroke were similar between PIONEER and SUSTAIN, there were disparate trends on CV death and MI between the trials (see just above) – PIONEER 6 also differs from LEADER (for liraglutide) on MI. He postulated that a difference in CV effects could arise through the different routes of administration, though this could also be a function of the relatively low number of events. Other important questions remain: How will oral semaglutide perform in the real world, particularly due to fasting requirements? Are there other drug interactions, and will fasting requirements make polypharmacy challenging? What is oral semaglutide’s impact on retinopathy? All of this said, Dr. Fonseca was very positive on the glycemic, weight loss, and CV efficacy as well as the safety and tolerability (slightly better than injectable semaglutide, in his assessment) of oral sema – suggesting that it even has the potential to replace all injectable GLP-1s.

Select Questions & Answers

Q: Have you looked at the impact of SGLT-2s specifically regarding MACE?

A: We haven’t specifically examined it, but if you read the discussion in the paper it does address their potential impact. Use was well balanced between the two treatment arms – there was a slight imbalance (during the trial – more SGLT2i usage in the placebo arm) - but I don’t believe it undermines the effects observed.

Q: In PIONEER 4, it seems semaglutide had a higher rate of serious adverse events vs. liraglutide. Did you mind any other side effects that were higher with semaglutide?

A: I think what you see in the trials as a whole is that there’s some variability in the rate of adverse events – in all clinical trials. The take home message is that adverse events are pretty well balanced against comparators and the rates of nausea and vomiting are consistent with the GLP-1 class.

Q: When it comes to responders and non-responders, I’d be interesting in knowing the subgroup of those defined by response. Is there gradation in risk for cardiac events?

A: With the prespecified subgroup analyses we did do, there was no obvious interaction (i.e. the p values for interaction were not-significant) suggesting that people with higher BMI, youngeror older, etc have different event rates. Again, it’s a relatively small number of events.

A: And reflecting across other studies, I don’t think anybody has a great angle on the characteristics of responders. To date, the benefit is largely in patients with prior CVD with the exception of the REWIND trial that had a large group without CVD.

Q: I’m interested in more details on CV death vs. ACM. About 1/3 to 25% have an undetermined cause of death; it might be useful to get a full list of causes of death in the trial because in ACM there could also be renal death or liver problems.

A: You’re right in that assessment; about 2/3 of deaths in both arms were cardiovascular deaths, and amongst this group there are some deaths of undetermined cause. With the events adjudication committee having no clues as to what may have happened in such deaths, it’s correct to assume that deaths of undetermined cause may be CV deaths. However, there’s no imbalance there, which is why I took care to show all causes of deaths. Any potential imbalance could have swayed the result one way or another. I don’t have an explanation for the non-CV deaths; there is a numerical difference, but those are the data.

Q: Is there any comparative data between oral and subcutaneous routes in serum levels at max or other doses?

A: I believe there has been a phase 2 study testing different oral semaglutide doses against SC semaglutide, with up to 20 mg oral being used; I believe this is how the PK/PD data established moving forward with the 14 mg oral dose. Based on the glycemic and weight loss efficacy we’ve seen presented at this symposium, we’re getting good active levels at 14 mg.

2. New CREDENCE Analysis Highlights Similar CV and Renal Risk Reduction in Primary vs. Secondary Prevention; Canagliflozin First SGLT-2 with Evidence of Primary Prevention MACE Benefit

Dr. Kenneth Mahaffey presented an exciting new CREDENCE analysis of outcomes by baseline CVD presence, showing consistent CV and renal outcomes in both primary and secondary prevention groups. On three-point MACE, canagliflozin treatment was associated with a 32% RRR (HR=0.68, 95% CI: 0.49-0.94) in the primary prevention group and a 15% RRR (HR=0.85, 95% CI: 0.69-1.06) in the secondary prevention group. This trend toward greater CV benefit in the primary prevention group is highly interesting and represents the first SGLT-2 inhibitor CVOT to show a nominally significant trend toward MACE benefit in such a patient population (CANVAS showed a HR=0.98 and DECLARE showed a HR=1.01 in their respective primary prevention subgroups). On the composite endpoint of CV death or hospitalization for heart failure, canagliflozin treatment was associated with a 26% RRR (HR=0.74, 95% CI: 0.54-1.03) in the primary prevention group and a 34% RRR (HR=0.66, 95% CI: 0.52-0.83) in the secondary prevention group. Renal outcomes were similarly consistent across primary and secondary prevention groups (see second image below).

• Very notably, the overall rates of the primary composite renal outcome were nearly identical between the primary and secondary prevention groups. This is in stark contrast to MACE, where events were obviously elevated in the secondary prevention group. Dr. Mahaffey highlighted this finding, and we note how this further justifies the earlier use of canagliflozin to achieve similar absolute risk reductions for renal outcomes in those with and without CVD. The risk/benefit profile of using canagliflozin in primary prevention groups (both for reducing CV and renal risk) appears to be highly favorable.

3. Tradjenta Reduces UACR Deterioration Regardless of Baseline eGFR, Confers Greater Improvement in UACR vs. Placebo; Slope of eGFR Decline Consistent Between Groups

University Hospital of Würzburg’s Dr. Christoph Wanner expanded on renal outcomes from CARMELINA (n=6,979), Lilly/BI’s CVOT for DPP-4 Tradjenta (linagliptin), revealing that Tradjenta conferred (i) lower rates of UACR deterioration regardless of baseline albuminuria status or eGFR and (ii) greater improvement in UACR, vs. placebo. As announced as EASD 2018, Tradjenta significantly reduced the risk of first occurrence of albuminuria progression (change from normo- to micro- or macroalbuminuria, or from micro- to macroalbuminuria) vs. placebo in CARMELINA (HR=0.86, 95% CI: 0.78-0.95, p=0.0034), completely driving significance on a larger microvascular composite endpoint. Today, Dr. Wanner confirmed that reduction was consistent across baseline albuminuria and eGFR subgroups. However, linagliptin may do more than prevent progression of albuminuria, as it actually demonstrated (i) significant improvement on time to first UACR reduction ≥50% in those with micro- or macroalbuminuria (HR=1.15, 95% CI: 1.07-1.25, p=0.0004) and (ii) improvement on sustained ≥50% albuminuria reduction in back-to-back visits (HR=1.10, 95% CI: 1.00-1.21, p=0.0394) vs. placebo in those with albuminuria. In the full study population, there was a greater chance of regression to normoalbuminuria with the DPP-4 (HR=1.20, 95% CI: 1.07-1.34, p=0.0021), though significance on this endpoint was lost when considering a sustained regression (HR=1.12, 95% CI: 0.98-1.28, p=0.0997). For both regression endpoints, results varied significantly by baseline eGFR (p-value for interaction=0.0315 for initial regression, p=0.0179 for sustained regression), demonstrating a most pronounced benefit in Stage 3a (eGFR ≥45 t0<60) and 3b (eGFR ≥30 to <45) CKD. Altogether, we find this important data when considering linagliptin’s potential in early prevention of CKD, particularly in those with albuminuria. In our view, the magnitude of linagliptin’s renal effects likely won’t blow anyone away (see below for details on the drug’s non-impact on eGFR), and we don’t expect a renal outcomes trial for any DPP-4. However, given the highly concerning incidence and prevalence of CKD and the contribution of diabetes to the disease, any therapies which improve UACR deterioration (which often precedes eGFR decline and subsequent end stage renal disease) are more than welcome. Of course, SGLT-2 inhibitors have become the new gold standard on this front – and we just saw compelling UACR data from DECLARE for Farxiga on Sunday – but more options to cater to the heterogeneity of type 2 diabetes population is always a good thing.

• The slope of eGFR decline was consistent between treatment groups: -2.3 mL/min/1.73 m² per year for placebo (95% CI: -2.5 to -2.1) vs. -2.5 mL/min/1.73 m² per year for linagliptin (95% CI: -2.7 to -2.3). The estimated difference came to -0.2 mL/min/1.73 m² per year (95% CI: -0.5 to 0.1, p=0.25). Of note, there was a faster eGFR decline in those with a baseline ≥60 mL/min/1.73m² regardless of study arm, but there was no significance in this rate of change regardless of treatment.

4. Two Dedicated NASH Sessions Review Diagnosis, Epidemiology, Current Treatment Options; Series of Orals Features SGLT-2s, PPAR Agonist, CVC, Tirzepatide

Dr. Michael Roden (Dusseldorf) chaired the first of two consecutive sessions featuring NASH. The symposium, “NASH – The Overlooked Complication of Type 2 Diabetes”, attracted a packed crowd to one of the Moscone Center’s largest rooms. Dr. Zobair Younossi began by offering “A Practical Review of Current Approaches” in NASH diagnosis. Using data generated by a number of studies, including NASH trials with biopsies, Dr. Younossi introduced a cost-effective algorithm comprised of fibrosis scores, liver stiffness measurements, and serum fibrosis tests to stratify patients into Low, High, and Indeterminate risk classes for NASH. Dr. Elisabetta Bugianesi (Milan) followed with “Impact of NASH in Type 2 Diabetes – Fact or Fiction? Should We Screen for NASH in Patients with Diabetes?” Dr. Bugianesi presented data suggesting 55% of patients with type 2 have NAFLD, a precursor to NASH, and that 37% have NASH. The burden of liver disease is also increasing dramatically, with end stage liver disease projected to increase 165% by 2030 (from 2015), reaching over 100,000 cases per year and accounting for over 75,000 deaths annually. Current US liver society guidance supports screening for NAFLD in patients with obesity, metabolic syndrome, or type 2; the major European societies only recommend screening for patients over 50 with type 2 or metabolic syndrome. This symposium concluded with Dr. Kenneth Cusi (U of Florida and “Treatment – Are We There Yet? Current and Upcoming Treatment Approaches”). Dr. Cusi’s perspective was evident from the heading of his first slide, “Treatment of NAFLD: A Call to Action.” He directly compared NASH to diabetic nephropathy in the 1980’s and osteoporosis in the 1990’s as a previously under-recognized condition associated with type 2 that needs treatments; however, unlike nephropathy and osteoporosis, NASH does not have a simple disease marker. His emphatic response to the rhetorical question of “Why diagnose if there are no pharmacological treatments” was to review the major non-pharmacological option (weight loss – very effective if at least 7% and ideally 10% of body weight, but only 10% of patients achieve this in studies), advocate for stronger AASLD endorsement of pioglitazone (Dr. Cusi and Dr. Ralph DeFronzo have published, both separately and together, on the long-term efficacy of pioglitazone in NASH for selected patients), and outline the potential of drugs currently under clinical development for NASH.  All three presentations were explicit about the need for greater coordination between diabetes and liver specialists. (We do not believe that primary care physicians are generally aware of NASH risks, and we wonder how quickly endocrinologists refer at-risk NASH patients to liver specialists.)

A second session of oral presentations featured five NASH-related studies; three reviewed data from approved diabetes drugs (dapagliflozin, empagliflozin, TZD), one from a drug in phase 3 for NASH (cenicriviroc), and one, from Lilly, presenting liver data on tirzepatide, currently under development in diabetes with announced plans for a phase 2 NASH study to start this year. Both dapagliflozin and empagliflozin were evaluated in 24-week studies of type 2 patients with NAFLD. Dr. Yoshimasa Aso (Dokkyo Medical University) concluded that dapagliflozin improves liver steatosis in parallel with a decrease in liver enzymes, and also attenuates liver fibrosis (measured via Fibroscan imaging). Dr. Sabine Kahl (German Diabetes Center) demonstrated that empagliflozin reduced liver fat (via MR imaging). In both studies, weight loss could account for the positive results. Dr. Cusi presented data on a novel insulin sensitizer (PPAR agonist) “with minimal PPAR-gamma activity maximized form mitochondrial pyruvate (MPC) modulation.” In interim (6 month) data from a 12-month NASH study (n=402) with liver biopsy, MPC modulation seems to improve multiple metabolic measures of type 2 and NASH, while reducing insulin resistance and avoiding peripheral edema, a TZD side effect. Final data is expected later this year. Dr. Mark Hartman of Eli Lilly presented data from tirzepatide’s (dual GIP and GLP-1 agonist) diabetes trial, which are promising for NASH. Tirzepatide had a positive effect on apoptosis, fibrogenesis, and inflammation markers; again, weight loss could be a confounding factor. Finally, Dr. Andrea Coviello of Duke presented data from Allergan’s phase 2b CENTAUR trial of cenicriviroc, specifically the antifibrotic effects which supported its subsequent phase 3 registration.

Exhibit Hall

Diabetes Technology

Abbott

The enormous Abbott booth (one of the largest we’ve ever seen at ADA) was divided between the US and international geographies, with the US portion advertising the 14-day FreeStyle Libre and the international section marketing the Bluetooth-enabled FreeStyle Libre 2 with optional hypoglycemia and hyperglycemia threshold alarms. Although the US representatives were unable to comment on FreeStyle Libre 2 timing, other than to confirm the device is under FDA review, they acknowledged that they had been receiving “lots of questions” from US attendees on when FreeStyle Libre 2 will be available. We learned from the international half of the booth that FreeStyle Libre 2 is currently available in Germany and Norway – the first signs of the gradual EU expansion anticipated after the initial Germany launch in October. For more on FreeStyle Libre 2 features and experience, see our coverage of Abbott’s product theater from Day #3.

Ascensia

The Ascensia booth stuck with the company’s bread and butter, marketing the Contour Next One meter with an emphasis on the target lights (green/red/yellow post-result), simplicity, and the Contour app’s pattern recognition. Reps alluded to Ascensia’s Interconnected Diabetes Management (IDM) program, which sounds as though it may be a CDE-driven subscription bundle program. IDM was mentioned at JPM, where we heard that it had wrapped up pilot studies through US medical centers in December, and was to move into commercial pilots in 2019. They also discussed Ascensia’s CGM play, a distribution agreement with Chinese CGM manufacturer POCTech. As of JPM, Ascensia is the exclusive distributor for POCTech’s CGMs in 13 markets (not specified), and ambitiously anticipates commencing sales of “Ascensia branded and boxed” CGM sensors “by the end of 2019” – we didn’t hear updates on the timing front.

Companion Medical

After a flurry of data partnership announcements in the week leading up to ADA (Dexcom, Glooko, and Rimidi), Companion had more updates to share in what was easily its largest exhibit ever. The Companion InPen app now pulls in Dexcom data through not only Apple Health, but also through the API for Android users (previously only iOS users could view their CGM data); Companion has made its API available, and Tidepool is among those who have begun pulling injection data; it is now possible to pair multiple InPens to the app (a big ask from the pediatric population who tend to like having pens in multiple locations); and minor tweaks to the Insight report in response to HCP feedback (e.g., it no longer assumes missed meal boluses, but pings the user to confirm that they did in fact eat and not bolus). It’s great to see Companion continuing to iterate in response to user requests and invest in critical software/interoperability improvements in this nascent category.

• Companion’s post-market study comparing InPen to traditional (non-connected) MDI, using FreeStyle Libre to assess time-in-range as the primary endpoint at three and six months, is still recruiting (n=60). The trial is taking place at Hoag Hospital under the direction of whip-smart, tech-savvy endo Dr. David Ahn. Results will hopefully read out later this year, though no exact timing was shared. 

Dexcom

Dexcom’s booth showed off G6 and Clarity, with a big bold sign: “Zero Fingersticks. Zero Scanning. First Interoperable CGM.” The booth had a larger-than-ever focus on the push to pharmacy distribution. Signs and flyers (see below) advertised a “Pharmacy First” message, building on Dexcom’s earlier “CGM First” campaign to encourage CGM prescription for MDIs. As of 1Q19, Dexcom had contracts in place for >50% of US covered lives in the pharmacy (including new addition Cigna), but far less than 50% of the business was actually flowing through the pharmacy (i.e., the vast majority of US sales are still through DME). Getting into the pharmacy clearly remains a focus to reduce hassle and compete with FreeStyle Libre, but it’s clear that even getting a majority of Dexcom’s business shifted to this channel will take quite a while. Our anecdotal experience getting G6 in the pharmacy (Aetna & Walgreens) has been challenging.

EOFlow

The EOFlow booth displayed it EOPatch pump, a three-day, disposable insulin patch pump with a 200U insulin reservoir. At just 23 g, the booth representative highlighted that EOPatch is “lighter than the competition” and can be programmed with eight different basal/bolus regimens. The pump is controlled with a dedicated controller and has a mobile app for viewing and sharing data. EOFlow CEO Mr. Jesse Kim anticipates an EOPatch launch in Korea in the next two-to-three months, aligning with EASD expectations for a 2H19 lunch. The company will submit EOPatch to the FDA later this year, hoping for a US launch in 2020. At EASD in October, EOFlow said it had already submitted to the FDA, implying timing is about a year delayed. As part of its JDRF-funded project to develop an all-in-one integrated closed loop system called EOPancreas, EOFlow will first develop a separate closed loop system (EOAPS) with its EOPatch pump, TypeZero (Dexcom) algorithm, and an unnamed CGM. EOFlow currently has a partnership with Chinese CGM company PocTech, but Mr. Kim hinted at the possibility of partnering with other CGM companies as well – Dexcom would be the obvious choice here, as it owns TypeZero. A clinical study testing EOAPS is set to begin this year in Columbia (an unconventional choice), to be followed by studies in Korea. Mr. Kim expects to launch EOAPS in Korea in 2020. While Mr. Kim could not comment on the details of the ongoing effort to develop EOPancreas, a prototype was on display.

Glooko

The Glooko booth included a demonstration of its Mobile Insulin Dosing System (MIDS) for titrating basal insulin in type 2 diabetes. Although MIDS has been FDA cleared since February 2018, a booth representative shared that it is only “just starting” to commercially launch. Glooko has agreements and pilots “with a handful” of clinics to slowly introduce MIDS. In taking this “soft launch approach,” Glooko hopes to gather and incorporate feedback from users before rolling out on a larger scale – very smart. We also learned more about Glooko’s recent involvement with T1D Exchange’s Quality Improvement Collaborative (QIC). As we reported earlier this week, Glooko will provide de-identified, aggregate data to T1D Exchange for the purposes of determining best practices across the QIC’s 11 clinics – prior to Glooko’s participation, T1D Exchange relied on EHR data only. This partnership will greatly expand T1D Exchange’s abilities to draw insights from the QIC. Glooko will not receive any of the data nor will it be responsible for analysis.

Glutalor

In a update from Glutalor’s iWel CGM data at ADA 2017, reps claims that the 10-day, factory-calibrated water-resistant CGM is CE-marked and will launch in the EU by the end of this year. The company hopes to receive FDA approval in 2Q20 and has already begun a pre-submission evaluation with the FDA. Glutalor will conduct a pivotal trial to support FDA submission in 185 adults and 185 children down to age two. In preparation of its EU launch, Glutalor is in discussions with BGM companies to help expand commercial reach – similar to what Sanvita/LifeScan and Ascensia/POCTech are doing. (Whether any of these off-the-radar CGMs actually make it market remains to be seen.) iWel has no separate insertion device: the sensor is loaded manually into the transmitter, which lasts six months, and then the entire device is inserted into the arm by manually pressing it in. Glucose readings are taken every three minutes and can be sent to “any smart device.” The booth representative emphasized that Glutalor can produce its sensor at a cost lower than any other player on the market, estimating that production is $1.50/sensor. The company’s new line can produce 5,000 sensors/day and is being moved to the US this week. Full production is slated by the end of July. The representative claimed that the sensor is small enough to be placed inside a patch pump. To this end, Glutalor is in discussions with pump and algorithm companies to potentially develop an integrated AID system. He pointed out that, given the low sensor cost, limiting sensor wear-time to three days for a patch pump would not be restrictive. According to advertising on the booth, the next gen CGM will be disposable and waterproof.

Glytec

At Glytec’s booth, we were eager to learn more about the pipeline, specifically the Therapy Advisor clinical decision support software. Per a press release last week, the company is actively engaged with FDA in the 510(k) process for the Therapy Advisor, which purports to optimize “all diabetes medications.” Taking into account guidelines from ADA, AACE, ACE, and EASD, as well as patient demographic and clinical data, the software will lead the HCP to two treatment recommendations and specify the pros and cons of each. Impressively, the system also aims to take into account patient ability and preferences, such as if they are on a weight loss program (solution: exclude products with weight gain side effect), if they have cognitive impairment (solution: exclude complex regimens), or if affordability is an issue (solution: direct to more cost-sensitive medications). It will even be able to use CGM data as the glycemic input.  This product could be a gamechanger for HCPs, assuming it lives up to the ambitious goals and can find a go-to-market business model. Still, this sort of decision support software could be fantastic, given HCPs’ limited time, all the patient factors in play, staying up to date on professional guidelines, and all of the therapy options now available. We see especially big potential for PCPs. We’re not sure when this could come to market. The most obvious correlate in our minds is Watson for Oncology, which infamously flopped despite big promising to recommend the best cancer treatments to doctors globally. Clinical decision support hasn’t quite taken off yet in diabetes; despite at least five FDA-cleared basal insulin titration apps and DreaMed’s FDA-cleared pump settings adjustment decision support system, commercial rollout and uptake have been limited – considering the number of clinics and patients who stand to benefit. How will this landscape look when Therapy Advisor is set to launch, and how can Glytec hit the ground running commercially?

Insulet

Insulet’s gleaming booth proudly advertised the US launch of Dash, the long-in-development Bluetooth-enabled PDM and pod that was FDA cleared one year ago and began its full market release in April. The Dash PDM is smaller and lighter in person than we remembered, with a terrific touchscreen user experience, friendly branding, and “podder” packaging. True to form, a sign at the top of the booth memorably gleamed, “Say goodbye to MDI,” and we expect Dash will help Insulet remain strong on MDI market expansion even as it takes time to catch up on automated insulin delivery. We had a chance to speak with Insulet’s Chief Commercial Officer Bret Christensen, who again confirmed that 50% of patients in the pharmacy have a <$35 copay for Dash – that includes the free PDM and often a 90-day supply of pods! In other words, many Dash users will pay less than $150 per year with no deductible for their pump supplies! Mr. Christensen emphasized that “Payers are loving” the 100% pay-as-you-go model – with no four-year lock in or major upfront cost – as it takes the financial risk out of paying for a pump. The average tenure of many payers’ patients is ~2.5 years, he told us; this makes four-year, multi-thousand-dollar investments in durable pumps a big ask. As of 1Q19, Insulet had coverage in place for 130 million lives – mostly in the pharmacy – meaning that ~1/3 US Omnipod users have access to Dash at launch. We expect Insulet’s Horizon hybrid closed loop will be the first AID system to launch in the pharmacy, quite a cool milestone.

LifeScan

LifeScan debuted its new OneTouch Delica Plus, a lancing device with 13-depth settings and 50% less vibration to provide “a virtually painless” experience. Delica Plus has been available in the EU for a “few months” and is expected to be available broadly in the US starting next month. Representatives were unable to comment on LifeScan’s recent agreement with Sanvita Medical to market and distribute Sanvita’s CGM products. Per the announcement in May, launches are expected in North America and select European countries as early as “mid-2020,” followed by expansion into other markets. Perhaps we’ll hear more details later this year at EASD.

Medtronic

Medtronic’s expansive booth had focused on the MiniMed 670G and latest real-world data (in ~120,000 users), with a notable video showing screenshots of its pipeline – including the MiniMed 780G advanced hybrid closed loop with automatic boluses (began pivotal trial on Day #2 of ADA; >80% time-in-range goal; launch ambitiously expected by ADA next year), Personalized Closed Loop (FDA submission in November 2020-April 2021), the Synergy fully disposable CGM (FDA submission in November 2020-April 2021), and the ambitious goal to make a combined seven-day-wear CGM/insulin infusion set (Project Duo). This is a very forward-looking, ambitious product plan and timeline. See our coverage of the Sunday’s Medtronic Diabetes analyst briefing for more details on these. A slide advertised that the new 670G transmitter has made it twice as easy to enter and stay in Auto Mode, driving 85% time in Auto Mode user in real-world use (comparing 30 days before vs. 30 days after launching the transmitter). A bar graph showed the rise in time-in-range with various therapies (see below), showing that 670G is the only one to reach above 70%. (Of note is that Tandem’s Control-IQ pivotal trial on Sunday also showed 71% time-in-range.) The marketing across the booth was strong, and we think Medtronic is moving full speed ahead in prompting more automated insulin delivery.

One Drop

One Drop has launched eight-hour glucose prediction for type 2s on basal insulin, those with prediabetes, and those with gestational diabetes (all iOS only), building on last fall’s launch of 12-hour forecasts (based on limited fingersticks) for type 2s not on insulin. Support for all people with diabetes on BGM or CGM (including basal-bolus) is expected “soon.” Within the glucose projection screen, the app displays a customizable target range, and indicates to the user how much time they are likely to spend in this range over the next eight hours. VP of Data Science Operations Dr. Dan Goldner told us that people will enjoy and respond to the gamified aspect; if they see that they are likely to spend 70% time in-range over the subsequent hours, they might adjust behavior or medication accordingly to boost that number higher – based on our experience with Dexcom’s Clarity, we very much agree with this. Nudges and suggestions from the app, such as “A short walk after a meal can reduce blood glucose levels,” could give the user a leg up in the “game” – we don’t get that now with Clarity and would love to! Indeed, we like this idea of tying communication to motivation and look forward to understanding the real-world accuracy and clinical impact. One Drop has a couple late-breaking posters at this ADA – 49-LB (on the 12-hour forecasts) and 48-LB (on A1c impact) – and we’ll return with coverage of those.  One Drop reps also foreshadowed movement into conditions beyond the current offerings of diabetes, prediabetes, and gestational diabetes, with future potential offerings for hypertension and hypercholesterolemia. The company will begin shipping connected weight scales and/or blood pressure cuffs to individuals who can benefit, following a trend set by Livongo, Omada, and others.

Senseonics

The Senseonics team was out in full force near the front door of the exhibit hall, celebrating its one-year anniversary of FDA approval for the 90-day implantable Eversense CGM. The crowded booth included sections dedicated to Eversense, Eversense XL (180 day), the Eversense Diabetes Management System (DMS) data platform for clinicians, and the Patient Access Bridge Program, plus an insertion/removal demo station – we found the latter particularly valuable. A cool Eversense bus was positioned at the back of the exhibit hall, equipped with two insertion/removal demo stations and plenty of representatives. Eversense just received the non-adjunctive dosing indication, just approved by the FDA on the eve of ADA. We expect that clinicians will become more aware of the approval once the updated app launches “early” in 4Q19, allowing patients to make dosing decisions with Eversense (which they are alredy doing) and, notably, enabling Medicare coverage – the latter is very exciting. For more on Senseonics’ pipeline, plus the first US Eversense real-world data, see Day #2.

SOOIL

At the SOOIL booth, we learned that the company expects to submit its Dana pump with smartphone control to the FDA this year – a likely delay from the company’s ATTD expectation for a US launch by end of 2019. SOOIL will submit Dana as an ACE pump and is in discussions with an insulin company regarding a pivotal trial. We weren’t surprised that the company’s bold promise at ADA 2018 to launch an open protocol, smartphone-controlled insulin pump in the US by ADA 2019 has not been realized. At the time, SOOIL’s Justin Walker claimed he was approached by the FDA at the JDRF/Helmsley interoperability workshop last April and asked to write the iPump protocol. Since then, Tandem’s t:slim X2 pump has become the first ACE (alternate controller enabled) “iPump” to be cleared by the FDA – we assume SOOIL did not play a role in informing the FDA’s (fairly straightforward) special controls for the ACE category. Importantly, SOOIL is no longer the only company planning to launch a pump with smartphone control in the near future: Tandem expects to receive FDA clearance for t:sport with smartphone control before the end of 2020; and Insulet plans to launch Omnipod Horizon hybrid closed loop in 2H20 with personal smartphone control, initially only on Samsung Galaxy phones. Medtronic is also working on smartphone control, though that is not slated until personalized closed loop (FDA submission until November 2020-April 2021).

Tandem

Tandem’s bright booth at the front of the exhibit hall advertised Basal-IQ, using the same tagline as we’ve seen since the US launch last August: “Basal-IQ predicts and helps prevent lows with zero fingersticks.” This is compelling! Screens dotted along the edge of the booth showed the upcoming secondary display mobile app for the t:slim X2 pump (see below), which looks fantastic – it combines t:slim X2 pump and Dexcom G6 CGM together. As of 1Q19, a launch of the app was expected this summer – perhaps by AADE? When we stopped by, reps were eagerly anticipating the Control-IQ pivotal trial results – which came out on Sunday and were excellent.

Tidepool

The Tidepool booth was modest in size but not in excitement, as reps detailed Tidepool Loop and Friday’s two new partner additions: Dexcom (G6) and Medtronic (future Bluetooth ACE pump and Guardian Sensor 3 iCGM) have signed on as official Tidepool Loop partners. At a panel during the middle of FDA, Tidepool CEO Mr. Howard Look said that Dexcom is the official CGM partner – presumably meaning it is the only available iCGM at the moment – though obviously future iCGMs will also integrate (Medtronic included, at least theoretically). Tidepool reps noted that enrollment in the Jaeb-run DIY Loop observational study shot up after DIY Loop became compatible with Omnipod; Mr. Look shared that >500 people have enrolled in the study at this point (the study’s target is 300-1,000). We estimate that >2,500 people are using the DIY Loop iPhone app globally; 75% of current orders are coming through to use Omnipods. 

Virta

Virta sported its first booth ever at a diabetes conference, a small exhibit on the periphery of the hall. In our conversations around the conference, some people had not yet heard of Virta and its low carb/high fat + continuous remote care intervention to put type 2 diabetes in remission – there was a lot of enthusiasm around the company in our discussions. Recently, the company published two-year data showing sustained engagement, weight and A1c reductions, diabetes “reversal,” and impressive medication elimination (especially in insulin users). We’re not sure how many people have enrolled/completed Virta’s program, but we learned that the company currently employs 25 health coaches and five MDs who administer remote care and medication optimization. This is part of the magic, that is for sure – from what we have heard, they are doing a very strong job making people feel successful. Each participant reportedly engages with coaches an average of 2-3 times monthly; for every 1,000 users, that means each coach is engaging in ~80-120 touchpoints per day. We also learned that Virta providers employ CGM through the clinic – they are not shipping CGM directly, but the MDs can prescribe assuming a patient is covered/wants to pay out-of-pocket. We hope they are using intermittent CGM, which is a great start for patients to understand where they are on the glycemic landscape.

Voluntis

Voluntis shared with us that Insulia’s (basal insulin titration app) NPH module has been CE marked and is under FDA review. Insulia is also currently piloting in the UK, and available in France, Germany, and Canada, in addition to a number of US states. The company is optimistic that new CPT codes for remote patient monitoring – 99453, 99454, and 99457 – will drive greater uptake from the provider side in the US. 99453 is for remote monitoring equipment setup and training, 99454 is for remote monitoring each thirty days; and 99457 is remote monitoring treatment management services (20+ minutes in a month). It remains to be seen if these codes will significantly shift the economics of caring for insulin-using patients, but any nudge, along with hands on support from the Voluntis team (clinic setup, remote patient onboarding), should move the needle in the right direction.

TeleDiab-2, a 13-month RCT comparing (i) an Insulia precursor with interactive voice interface, (ii) the precursor app; and (iii) standard care in 191 type 2s initiating basal insulin, was published in Diabetes, Obesity, and Metabolism three days ago. The algorithm recommended daily adjustments of basal insulin doses to target a fasting blood glucose of ~100 mg/dl. Both groups with basal titration saw significantly greater reductions in A1c (-1.44% with the voice interface and -1.48% with the app) than the standard care group (-.92%). Mild hypoglycemia was similar across groups. The study system isn’t exactly the same product as Insulia, but it still supports the efficacy of basal insulin titration generally, as well as Voluntis’ app (think positive data in a study of Dexcom G4 CGM supporting G6 efficacy). 

-- by Adam Brown, Ann Carracher, Martin Kurian, Brian Levine, Peter Rentzepis, Maeve Serino, and Kelly Close