June 10-14, 2016; New Orleans, LA; Full Report – Insulin Therapy – Draft

Executive Highlights

This document contains our coverage of insulin therapy at ADA 2016. Immediately below, we enclose our themes on the category, followed by detailed discussion and commentary. Talk titles highlighted in yellow were among our favorites from ADA 2016; those highlighted in blue are new full report additions from our daily coverage.

For comprehensiveness, we have included some talks in this report that also overlap with our ADA 2016 GLP-1 Agonist report.

Themes

• New rapid-acting insulin analogs stepped into the spotlight at ADA 2016, following several years in which basal insulins stole the show. Innovation in the rapid-acting insulin analog field has occurred at a somewhat slower pace compared to the basal insulin field that recently saw the US launches of next-generation options from Sanofi (Toujeo [U300 insulin glargine]) and Novo Nordisk (Tresiba [insulin degludec]). Like Toujeo and Tresiba, the next-generation rapid-acting insulin analogs seem to offer meaningful but incremental benefits over existing products but are not expected to be paradigm-shifting innovations. Many of the most notable rapid-acting insulins are variations on existing insulins, rather than entirely new molecules. The data we’ve seen thus far suggest that the new products offer significant but modest improvements in postprandial glucose control, are non-inferior or very modestly superior in terms of A1c reduction, and produce comparable or slightly improved hypoglycemia rates compared to current rapid-acting analogs. Perhaps most excitingly, it appears that the next-generation products may retain their efficacy with mealtime or even post-mealtime dosing, as opposed to the 15 minutes pre-mealtime dosing recommended with the current rapid-acting insulins. This potential for greater dosing flexibility should be very meaningful for patients, as it is more consistent with how many patients dose mealtime insulin in the “real world.” 
  
  • The most advanced next-generation insulin analog is Novo Nordisk’s faster-acting insulin aspart, which presented full phase 3 Onset 1, Onset 2, and Onset 3 data at ADA 2016. Onset 3 found that intensification to a basal-bolus regimen with faster-acting aspart in patients with type 2 diabetes resulted in a statistically superior mean A1c reduction of 0.94% (baseline A1c=7.9%; p<0.0001) compared to continued treatment with basal insulin alone. In a head-to-head comparison, Onset 2 found that faster-acting insulin aspart administration in patients with type 2 diabetes produced non-inferior A1c reductions and significant improvements in postprandial control compared to Novo Nordisk’s NovoLog (insulin aspart). A1c dropped from 8% to 6.6% with faster aspart and from 7.9% to 6.6% with NovoLog. Faster aspart produced a significant 10.6 mg/dl improvement in one-hour postprandial glucose (p=0.0198) and a numerical but not significant improvement of 6.6 mg/dl in two-hour postprandial glucose. In patients with type 1 diabetes, Onset 1 found a modest but statistically significant improvement in A1c with Faster aspart (~0.2% vs. standard aspart). Notably, in addition to the modest A1c benefits, two-hour postprandial blood glucose levels were superior with Faster aspart than regular aspart (by ~12 mg/dl), and, in terms of A1c reduction, post-meal Faster aspart administration was non-inferior compared to standard pre-meal administration of current insulin aspart.
  • Adocia offered a glimpse at phase 1b meal study results for its Lilly-partnered BioChaperone Lispro and its BioChaperone Combo (insulin glargine/insulin lispro). Both demonstrated improvements in one-hour and two-hour postprandial glucose compared to Lilly’s Humalog (insulin lispro). BioChaperone Lispro demonstrated a mean glucose difference of 42 mg/dl one hour post-meal and a mean difference of 27 mg/dl two hours post-meal. BioChaperone Combo reduced postprandial glucose excursions by 24 mg/dl at one hour compared to Humalog. BioChaperone Combo produced numerically fewer hypoglycemic episodes compared to Humalog and was associated with more time in range. Hypoglycemia was comparable between BioChaperone Lispro and Humalog.
  • MannKind’s Afrezza (inhaled insulin) also demonstrated improvements compared to Lilly’s Humalog (insulin lispro) in terms of a faster onset and shorter duration of action. Afrezza is one of the few new rapid-acting insulins that arguably represents a true, groundbreaking innovation, given its unique delivery method. Unfortunately, burdensome prescribing requirements and potential safety concerns related to the novelty of the product have led to sluggish uptake for Afrezza in the year and a half since its launch. The product has been further plagued by Sanofi’s decision to terminate its licensing agreement with MannKind for Afrezza and MannKind’s CEO woes in the early half of this year. That said, many patients on Afrezza extoll its benefits and we believe that the hurdles presented by the prescribing requirements and other concerns can be mitigated. MannKind appears committed to keeping Afrezza available and announced during ADA that it intends to partner with JDRF to investigate Afrezza for a pediatric population.
• There’s new and then there’s “new” insulins – we saw results from phase 3 trials of Merck/Samsung’s biosimilar insulin glargine MK-1293 and Sanofi’s biosimilar insulin lispro SAR342434 for the first time. In an oral and a poster presentation, MK-1293 demonstrated similar efficacy and safety to Sanofi’s Lantus (insulin glargine) in both patients with type 1 and type 2 diabetes over 24 weeks. Merck recently shared that it has filed MK-1293 in Europe and we presume a US filing will follow soon. MK-1293 will likely be the second biosimilar insulin glargine to market, after Lilly/BI’s Basaglar/Abasaglar that has already launched in multiple ex-US markets and will launch in the US in December 2016. Biocon/Mylan also have a biosimilar insulin glargine in the works that they hope to file in the US and EU in the next few months. On the rapid-acting insulin side, Sanofi’s biosimilar insulin lispro SAR342434 demonstrated similar effects on A1c and postprandial glucose excursions with a similar safety profile as Lilly’s Humalog (insulin lispro) in combination with Sanofi’s Lantus (insulin glargine) in patients with type 1 diabetes.
• The basal insulin front was comparatively quiet at this year’s ADA. Most notably, in a series of late-breaking posters, we saw full SWITCH 1 and SWITCH 2 results demonstrating a hypoglycemia benefit for Novo Nordisk’s Tresiba (insulin degludec) over Sanofi’s Lantus (insulin glargine). Novo Nordisk plans to submit this data to the FDA soon, in the hopes that it will support some sort of language surrounding reduced risk of hypoglycemia in Tresiba’s label.

Detailed Discussion and Commentary

Oral Presentations: Treatment Choices after Orals in Type 2 Diabetes

Clinical Impact of Titratable Fixed-Ratio Combination of Insulin Glargine/Lixisenatide vs. Each Component Alone in Type 2 Diabetes Inadequately Controlled on Oral Agents: LixiLan-O Trial

Julio Rosenstock, MD (University of Texas Southwestern Medical Center, Dallas, TX)

Dr. Julio Rosenstock presented results from the phase 3 LixiLan-O trial demonstrating significantly greater A1c reductions with Sanofi’s iGlarLixi (formerly LixiLan) vs. either of its components in patients with type 2 diabetes on oral agents. Sanofi announced topline results from the trial in July 2015 and the dataset was included in the company’s briefing documents for the recent FDA Advisory Committee meeting for iGlarLixi. The open-label trial randomized 1,170 patients with type 2 diabetes not at goal on metformin and another oral agent to receive either iGlarLixi (n=469), Lantus (insulin glargine; n=467), or lixisenatide (n=234) for 30 weeks. A1c reductions were significantly greater with iGlarLixi (1.6%) vs. both Lantus (1.3%) and lixisenatide (0.9%) (baseline = 8.1%; p<0.0001). A significantly higher percentage of patients achieved an A1c <7% with the combination (74%) compared to Lantus (59%) and lixisenatide (33%). Fasting plasma glucose reductions were comparable with iGlarLixi (62 mg/dl) and Lantus (59 mg/dl) and less impressive with lixisenatide (27 mg/dl) (baseline = 176-178 mg/dl; p<0.0001). As expected, lixisenatide’s greatest contribution was on postprandial glucose. iGlarLixi was superior to both Lantus (by 43 mg/dl) and lixisenatide (by 20 mg/dl) on two-hour postprandial glucose; the combination was superior to Lantus (by 38 mg/dl) but inferior to lixisenatide (by 16 mg/dl) on postprandial glucose excursions. Seven-point glucose profiles showed lower overall glucose throughout the day with iGlarLixi and lower peaks compared to Lantus, especially at breakfast. The combination also demonstrated a 1.4 kg weight benefit compared to Lantus and allowed a significantly higher percentage of patients to achieve the composite endpoint of A1c <7% with no weight gain (43% vs. 25% with Lantus and 28% with lixisenatide).

• Especially relevant in light of the AdComm discussion, Dr. Rosenstock highlighted the potential for dosing flexibility with the two iGlarLixi pens. Sanofi plans to market iGlarLixi in two pens, one (pen A) with a 2:1 insulin glargine/lixisenatide ratio and insulin doses ranging from 10-40 U/day and another (pen B) with a 3:1 insulin glargine/lixisenatide ratio and insulin doses ranging from 40-60 U/day. Dr. Rosenstock emphasized that this allows insulin titration up to 60 U without going above the maximum dose of 20 mcg lixisenatide. Data on the final dose distribution in LixiLan-O showed that 56% of patients achieved good control with pen A, 44% required intensification to pen B, and only 8% reached the maximum dose of 60 U without achieving target. A number of panelists at the AdComm meeting expressed concerns about distinguishing between the two pens and about the nomenclature of “units” used to dose the combination. These concerns were fairly unexpected to us, and we hope Sanofi and the FDA can work together to resolve them in short order.
• Adverse events were generally similar between groups in the trial. Nausea rates were substantially lower with iGlarLixi (9.6%) compared to lixisenatide (24%), confirming one of the main expected with these combinations compared to GLP-1 agonists alone. Dr. Rosenstock highlighted the fact that only 0.4% of the iGlarLixi group discontinued treatment due to nausea (compared to 2.6% in the lixisenatide group). The rate of documented symptomatic hypoglycemia was low and comparable between the iGlarLixi and Lantus groups (1.4 vs. 1.2 events/patient-year).

Questions and Answers

Q: Given the short duration of action of lixisenatide, might it make more sense to use it twice a day?

A: That sounds like common sense but you don’t need to. With the results you get, why would you need to? You get an effect on postprandial glucose mainly in the morning, you do have some carry over for lunch, and by dinner there’s not much, but you get down to 6.5%. We shouldn’t use it twice a day because it’s not approved.

Q: Would you use it twice a day if A1c deteriorates over time?

A: I don’t know. We need longer-term studies.

Q: I’d like to see a study where you challenge the fixed-ratio combination not only to glargine + lixisenatide but to degludec + liraglutide, comparing the fixed ratio with split injections. I think it would highlight the convenience of the fixed ratio and on the other side the ability to individualize the combination because we know patients have different characteristics.

A: There’s no question that what you suggest would be a nice study. The question is whether simultaneous therapy is better than sequential. All these years we’ve done sequential. We have a bit of indirect evidence on this from GetGoal Duo 1, where patients were on basal insulin for 12 weeks and then added lixisenatide. That got people down to 7% and here we got down to 6.5%. The important bottom line is that we get down to 6.5%. The same was true with IDegLira. Both combinations get people down to levels we were never able to get before with any of the components alone.

Q: What concentration of insulin glargine was used?

A: U100.  

Oral Presentations: Beyond Basal Insulin in Type 2 Diabetes – Treatment Intensification Options

Efficacy and Safety of the Insulin Glargine/Lixisenatide Fixed-Ratio Combination vs. Insulin Glargine in Patients with T2DM: The LixiLan-L Trial

Vanita Aroda, MD (MedStar Health Research Institute, Hyattsville, MD)

Dr. Vanita Aroda presented results from the phase 3 LixiLan-L trial demonstrating significantly greater A1c reductions with Sanofi’s iGlarLixi (formerly LixiLan) vs. Lantus (insulin glargine) in patients with type 2 diabetes on basal insulin, driven by improvements in postprandial glucose. Sanofi announced topline results from the trial in September 2015 and the dataset was included in the company’s briefing documents for the FDA Advisory Committee meeting for iGlarLixi. The open-label trial randomized 736 patients not at goal on basal insulin and oral drugs to treatment with iGlarLixi (n=367) or Lantus (n=369) for 30 weeks. The insulin glargine dose in both groups was titrated to a fasting glucose target of 80-100 mg/dl and the dose was capped at 60 U/day (to match the maximum dose in the combination). A1c reductions were significantly greater with iGlarLixi (1.2%) than Lantus (0.6%) (baseline = 8.1%). A significantly higher percentage of patients achieved an A1c <7% with iGlarLixi (55%) than with Lantus (30%; p<0.0001). Fasting plasma glucose reductions were similar in both groups (21 mg/dl vs. 23 mg/dl), as expected given the almost identical average daily doses of insulin glargine at the end of the trial (46 vs. 47 U). The main contribution of lixisenatide to the combination was on postprandial glucose: iGlarLixi produced significantly greater reductions in both two-hour postprandial glucose (85 mg/dl vs. 25 mg/dl) and postprandial excursions (70 mg/dl vs. 8 mg/dl) compared to Lantus. Seven-point glucose profiles illustrated this improvement in postprandial control, particularly after breakfast. iGlarLixi led to a 1.4 kg weight benefit and comparable hypoglycemia rates to Lantus. The combination also allowed a greater percentage of patients to achieve an A1c <7% without weight gain (34% vs. 13%), an A1c <7% without hypoglycemia (32% vs. 19%), and an A1c <7% without weight gain or hypoglycemia (20% vs. 9%) – while the benefit is encouraging, the low absolute percentages in both groups illustrate the remaining need for more effective therapies.

Questions and Answers

Q: Do you think the weight loss is less when lixisenatide is used in combination with insulin vs. separately when added to insulin or without insulin?

A: I would refer you to the LixiLan-O trial, where we saw greater weight loss with lixisenatide alone. Here we have mitigation of the weight gain with insulin glargine.

Q: But the average weight loss seems to be less here than when you add on a GLP-1 agonist without insulin or even separately.

A: Part of it might be the final dose, which was 17 mcg of lixisenatide on average.

Q: I’m guessing the combination was administered before breakfast. Was the administration of glargine alone done at the same time?

A: Glargine could be administered at any time and it was consistent throughout the trial. The combination was injected an hour before breakfast.

Q: From the seven-point profile, it’s obvious that the main effect is on that first meal, yet it was a fixed schedule of dosing before breakfast. Do you think the results would be different if it was administered with the largest meal rather than breakfast? My patients don’t all eat breakfast, and dinner is typically the biggest meal in the US.

A: That’s an intriguing question that can only be answered by a trial. There was a sub-study looking at dosing at the main meal vs. the morning and the main effect seems to be in the morning, but we would need a trial to know.

Q: You didn’t save a single dose of insulin by adding lixisenatide and you had the same rate of hypoglycemia. Is there any information on the PK/PD data? Were the profiles of both components really preserved? It seems like a very weak effect.

A: The PK data were consistent with what was seen in the lixisenatide standalone program. Your point is appreciated that there’s not necessarily an insulin-sparing effect. I would also state here that we had a greater A1c reduction down to 6.9% without increased hypoglycemia. We’re looking at two different end A1cs with comparable hypoglycemia.

Q: Looking at the meal data in the control group, you still have glucose values of 230 mg/dl two hours after a meal – people are clearly not well controlled. Would you anticipate different results if you had a more well-controlled group?

A: The 230 mg/dl was from a mechanistic substudy highlighting the mechanism of action of iGlarLixi on postprandial glucose. The 7-point SMPG, reflective of control in the comparator group, showed the control we typically see with titration with insulin glargine (postprandial glucose of 160s-190s during the day). This, along with detailed review of titration, superimposable fasting glucoses, and insulin doses all support appropriate titration in the control group.

Faster-Acting Insulin Aspart vs. Insulin Aspart as Part of Basal-Bolus Therapy Improves Postprandial Glycemic Control in Uncontrolled T2D in the Double-Blind onset 2 Trial

Keith Bowering, MD (University of Alberta, Edmonton, Alberta, Canada)

Dr. Keith Bowering presented results from the phase 3 Onset 2 trial demonstrating non-inferior A1c reductions and significant improvements in postprandial control with Novo Nordisk’s faster-acting insulin aspart vs. NovoLog (insulin aspart) in patients with type 2 diabetes. The double-blind study enrolled 689 patients who were randomized to receive either faster aspart or NovoLog for 26 weeks in addition to Sanofi’s Lantus (insulin glargine) and metformin. A1c reductions were comparable in both groups: A1c dropped from 8% to 6.6% with faster aspart and from 7.9% to 6.6% with NovoLog. Faster aspart produced a significant 10.6 mg/dl improvement in one-hour postprandial glucose (p=0.0198) and a numerical but not significant improvement of 6.6 mg/dl in two-hour postprandial glucose. Fasting glucose and three- and four-hour postprandial glucose was comparable in both groups, and both products led to a 2.7 kg weight gain. Adverse event rates and overall hypoglycemia rates were also balanced; there were numerically more severe hypoglycemia events in the faster aspart group (27 vs. 17 events), but Dr. Bowering explained that 18 of the events in the faster aspart group occurred in the same three patients, likely skewing the results. These results are consistent with our sense that faster aspart offers a real but incremental improvement over existing rapid-acting insulins. The improvement in postprandial glucose and the potential for more dosing flexibility should be meaningful for many patients, but we do not expect faster aspart to be a transformational therapy in the same league as other Novo Nordisk products like Xultophy (insulin degludec/liraglutide) and semaglutide.

Questions and Answers

Q: You started by showing area under the curve for the first 30 minutes. You didn’t show more classical endpoints like total area under the curve or Cmax. Do you have any data on that?

A: That is available in a poster here. I believe Cmax was 10 minutes earlier than standard aspart.

Q: What was the time between the injection of insulin and the start of the meal? Could the dosing be more flexible? Based on the Biodel studies, there might be less late hypoglycemia. Did you see anything like that?

A: They were supposed to inject within two minutes of a meal. There was a small number of hypoglycemic events in the first two hours, and in that time frame there was more hypoglycemia seen with faster aspart than standard aspart. Those numbers were small in comparison with the later events.

Adding Faster-Acting Insulin Aspart to Basal Insulin Significantly Improved Glycemic Control: The Onset 3 Trial

Helena Rodbard, MD (Endocrine and Metabolic Consultants, Rockville, MD)

Dr. Helena Rodbard (Endocrine and Metabolic Consultants, Rockville, MD) presented results from the Onset 3 trial of Novo Nordisk’s faster-acting insulin aspart in patients on basal insulin. The 18-week, open-label, parallel group trial (n=236 patients with type 2 diabetes on basal insulin therapy) found that intensification to a basal-bolus regimen with faster-acting aspart resulted in a statistically superior mean A1c reduction of 0.94% (baseline A1c=7.9%; p<0.0001) compared to continued treatment with basal insulin alone. Furthermore, 60% of those in the faster-acting insulin aspart group achieved an A1c <7% at the end of the 18 weeks (compared to 18% in the basal-only group, p<0.0001) and 45% achieved an A1c ≤6.5% (compared to 7% in the basal-only group, p<0.0001). Even more impressively, in the faster-acting insulin aspart group, 59% were able to achieve the target A1c <7% without experiencing severe hypoglycemia (compared to 7% with basal-only, p<0.0001) and 43% were able to achieve the target A1c ≤6.5% without experiencing severe hypoglycemia (compared to 7% with basal-only, p<0.0001). 8-point SMPG profiles indicated improved glycemic control with faster-acting insulin aspart at all points in throughout the day. Regarding postprandial glucose (PPG) specifically, 81% of participants taking faster-acting insulin aspart were able to achieve a PPG ≤140 mg/dl (compared to 22% in comparator arm, p<0.0001) and 80% were able to do so without severe hypoglycemia (compared to 21% in comparator arm, p<0.0001). Fasting plasma glucose (FPG), on the other hand, was not significantly different between the two arms. As expected and consistent with prandial insulin intensification, adverse events included weight gain (mean weight gain=1.66 kg in the faster-acting insulin aspart group) and increased rate of hypoglycemia.

Oral Presentations: Novel Therapeutics in Type 1 Diabetes

Double-Blind Mealtime Faster-Acting Insulin Aspart vs. Insulin Aspart in Basal-Bolus Improves Glycemic Control in T1D: The Onset-1 Trial

David Russell-Jones (Royal Surrey County Hospital, University of Surrey, UK)

Dr. David Russell-Jones gave us our first full look at results from the Onset 1 trial, which examined Novo Nordisk’s faster-acting insulin aspart formulation (Faster aspart) in type 1 diabetes. As a reminder, Novo Nordisk shared topline results from Onset 1 & 2 in early 2015 and submitted Faster aspart to the FDA at the end of last year. Onset 1 found a modest but statistically significant improvement in A1c with Faster aspart (-0.17% vs. standard aspart) with no increase in severe or confirmed hypoglycemia. In our view, among the most important findings among the new data were: (i) in addition to the modest A1c benefits, two-hour postprandial blood glucose levels were superior with Faster aspart than regular aspart (by ~12 mg/dl), and (ii) in terms of A1c reduction, post-meal Faster aspart administration was non-inferior compared to standard pre-meal administration of the current insulin aspart. The latter finding makes for a pretty cool claim and stands to make a difference for patients who find it challenging to consistently take their insulin pre-meal, though it bears remembering that although post-meal Faster aspart was comparable with pre-meal NovoLog, pre-meal Faster aspart was still the winner in this trial.

• Study design: Onset 1 randomized 1,143 type 1 diabetes patients on basal-bolus therapy with Levemir (insulin detemir) and NovoLog (insulin aspart) to either stay on that treatment regimen, switch the NovoLog for Faster aspart dosed pre-meal, or to switch to Faster aspart dosed post-meal. The main portion of the trial ran for 26 weeks. Average age at baseline was in the mid-40s, with a mean BMI around 26 kg/m² and mean A1c of 7.6%.

Questions and Answers

Q: Was the total dose at the end of the study similar?

A: Yes, they were similar across groups. Because of continuous bolus titration, there was a slight increase from baseline in bolus dose after titration.

Q: Was the insulin dosed at the time of the meal or 20 minutes before?

A: At the onset of the meal.

Q: I would have expected that the Faster aspart group might have had less delayed hypoglycemia if it is more rapid-on, rapid-off. Was there any CGM data?

A: There was no difference in nine-point profiles.

Q: I’m surprised that insulin doses were adjusted based on premeal glucose, because the main benefit was post-meal. Wouldn’t you expect better results if you targeted post-meal control rather than premeal results?

A: I think in clinical trials, post-meal glucoses are much more variable. It’s safer to do protocol as defined. As you can see, people did see a reduction in A1c.

Q: Did you see any benefits in hypoglycemia immediately post-meal?

A: Overall, the rate of hypoglycemia was similar. If you were going to have a hypoglycemic episode right at the beginning, which is a pretty low proportion of overall cases, you had a slightly higher chance with Faster aspart, which you would expect. But the overall rate was incredibly low.

Q: How should we think about nutrient matching with this insulin? What would happen with a high fat meal, or someone who is a very marked carbohydrate restrictor? Would that potentially lead to a dangerous risk of hypoglycemia early after the meal?

A: The short answer is that those studies have not yet been done. Although Faster aspart is incrementally faster, it’s only by degrees. In practicality, I don't think that would be a problem.

Q: Why didn't you test both insulins with post-meal administration?

A: What I think is important is that this trial shows that if you use Faster aspart after a meal, you still get as much benefit as if you took ordinary aspart before the meal. A lot of patients do this sometimes, so I think this is an important finding.

Q: What about stability in insulin pumps?

A: This insulin is going to be extremely useful for people on pumps. The pump PK data is very impressive. There are a large number of pump studies ongoing, and I suspect that it will be a topic for next year’s ADA.

Efficacy and Safety of MK-1293 Insulin Glargine Compared with Originator Insulin Glargine (Lantus) in Type 1 Diabetes (T1D)

Philip Home, DPhil (Newcastle University, Newcastle Upon Tyne, UK)

Professor Philip Home presented phase 3 data showing that Merck’s Samsung-partnered biosimilar insulin glargine MK-1293 demonstrated similar efficacy and safety to Sanofi’s Lantus in people with type 1 diabetes. Professor Home presented the 24-week data of this phase 3, active-controlled, open-label, 52-week study, in which 506 participants with type 1 diabetes were randomized 1:1 to once-daily MK-1293 or Lantus, guided by a fasting glucose-based dosing algorithm. At week 24, from a baseline A1c of ~8%, the MK-1293 and Lantus groups achieved A1c reductions of 0.65% and 0.68%, respectively, meeting the non-inferiority and equivalence criteria with a difference of only 0.03%. Total insulin dose between the two arms was also similar, with the MK-1293 group on 49.4 U/day vs. the Lantus group’s 50.4 U/day. Basal and prandial insulin doses between the arms differed by 0.8 U/day and 2.3 U/day, respectively. Regarding fasting plasma glucose, MK-1293 and Lantus arms achieved reductions of 16.4 mg/dl and 25.9 mg/dl, respectively. Professor Home noted that this relatively larger difference may be due to the not-so-reliable measure of the clinic samples and pointed to the 7-point average SMPG difference as more consistent (-4.9 mg/dl for MK-1293 vs. -4.6 mg/dl for Lantus), as he called for regulators to consider CGM approaches for these measures in the future. As for the safety profile, the difference of percentage of participants experiencing symptomatic hypoglycemia remained small, with 71% and 76% of the MK-1293 and Lantus groups, respectively. Professor Home pointed out an imbalance in severe hypoglycemia (6.1 events/person-year in MK-1293 vs. 3.2 in Lantus), but highlighted that only two participants on MK-1293 were accounting for 49% of the severe episodes. For other adverse events, there were minimal treatment group differences (241 events in MK-1293 vs. 248 events in Lantus) and the anti-insulin antibody (AIA) response was similar between the two arms, with regards to cumulative incidence, neutralizing antibodies, and immunological insulin resistance. Thus, Professor Home concluded that the overall therapeutic profile of MK-1293 was similar to that of Lantus in type 1 diabetes.

• As background, Merck recently shared that MK-1293 is filed in Europe; the candidate is one of the first three insulin glargine biosimilars (the other two being from Lilly/BI and Biocon/Mylan) and while we have not explicitly heard plans for a US filing, we would expect one to come soon alongside Europe’s. These data are certainly promising and we continue to express cautious hope that the movement of biosimilars into the market will cut down on the increasing costs of insulin for patients – we also wonder, of course, how much providers will trust these new formulations.

BioChaperone® Combo (BC Combo) Improves Postprandial Glycemia vs. Humalog® Mix 75/25™ (HMx) in People with Type 1 Diabetes Mellitus (T1DM)

Steve Edelman, MD (UCSD, San Diego, CA)

Dr. Steve Edelman presented new phase 1 data of Adocia’s BioChaperone Combo (insulin glargine/insulin lispro), demonstrating superior postprandial glycemic control compared to Lilly’s Humalog (insulin lispro) in people with type 1 diabetes. In this double-blind, randomized, crossover mixed-meal study (ClinicalTrials.gov Identifier: NCT02514954), 28 participants with type 1 diabetes (baseline A1c of 7.3%) received equivalent individualized doses of BioChaperone Combo or Humalog, immediately prior to a standardized meal (508 kcal [68 g], 56% carbs/17% protein/27% fat). Looking at the six-hour post-meal glycemic profiles, Dr. Edelman showed that starting from identical baseline blood glucose levels, BioChaperone Combo reduced post-meal blood glucose over two hours and had a lower blood glucose maximum compared to Humalog (72 mg/dl vs. 95 mg/dl), as well as a reduced PPG excursion at one hour (-24 mg/dl) compared to Humalog. Within the first two hours, BioChaperone Combo also had a comparative 24% reduction in post-prandial glucose excursions (as measured by glucose area under the curve, p=0.008). In addition, the Humalog arm experienced a late post-prandial blood glucose drop below baseline ~3.5 hours post-meal (BioChaperone Combo dropped below baseline at around 5.5 hours) and those on Humalog had a lower blood glucose minimum compared to the BioChaperone Combo group (65 mg/dl vs. 94 mg/dl). Regarding hypoglycemia, the Humalog group experienced numerically more hypoglycemic episodes than the BioChaperone Combo group (15 vs. 9 for ≤70 mg/dl; 8 vs. 4 for ≤50 mg/dl), as the BioChaperone Combo group spent more time in target (80 to 180 mg/dl) with 274 minutes vs. 183 minutes. On safety and tolerability, Dr. Edelman noted that there were no significant differences between treatment groups’ safety profiles with three adverse events reported in each group (mostly consisting of headaches, nausea, and flu-like symptoms) and the treatments proved to be well-tolerated with no injection site reactions. This study is one of several trials that Adocia is conducting on its insulins, as the company has also recently initiated phase 1b studies for its HinsBet (BioChaperone human insulin) and BioChaperone Lispro. These new promising findings for BioChaperone Combo prompt us to continue wondering if the product could potentially be incorporated into the Lilly partnership – please see our Adocia 1Q16 report for more on the company’s latest.

Questions and Answers

Q: How do you anticipate to see this clinical benefit?

A: To me, as someone who sees patients quite a bit, you have a more effective reduction in PPG and you have a reduced rate of delayed hypo. As you know, using current premixes, they do have a rapid acting analog but combined with insulin, they have the same PK/PD profile as NPH. This’ll impact the timing of injections and lead to hypo. And those insulins don’t last as long. Similar to the Novolog product, these types of premixes will be great for type 2 diabetes. I think that’s why a lot of clinicians don’t use these premixes – because of the PK/PD.

Q: Was it a solid or liquid meal test?

A: It was a solid meal. It was prepared in kitchen with 69 grams of carbs, proteins, and fats. It was an Italian meal.

Q: Anything done to impact the timing of the glargine component?

A: As I understand it, these molecules are basically the same. But when you put them in a combo through this technology, the time course may change. The most obvious was the lispro. I do believe that it’s the nature of the bonding of these molecules that allow the PK/PD to be different. The molecules themselves are unchanged. It’s the combo through this technology that’s affecting it.

Ultra-Rapid BioChaperone Lispro Ameliorates Postprandial Blood Glucose (PPG) Control Compared with Humalog in Subjects with Type 1 Diabetes Mellitus

Tim Heise, MD (Profil GmbH, Neuss, Germany)

Dr. Tim Heise (Profil GmbH, Neuss, Germany) presented results from a phase 1b meal study showing greater improvements in postprandial glucose with Lilly/Adocia’s ultra-rapid BioChaperone Lispro compared to Lilly’s Humalog (insulin lispro). The single-center, double-blind, randomized, single-dose, cross-over study in patients with type 1 diabetes (n=38, baseline A1c=7.4%) found that mealtime BioChaperone Lispro administration resulted in a mean one-hour postprandial glucose (PPG) difference of 42 mg/dl compared to mealtime Humalog administration (mean one hour PPG=135 mg/dl with BioChaperone Lispro vs. 177 mg/dl with Humalog, baseline blood glucose=100 mg/dl). Two-hour PPG was also lower with BioChaperone Lispro compared to Humalog, with a mean difference of 27 mg/dl (mean two-hour PPG=126 mg/dl with BioChaperone Lispro vs. 153 mg/dl with Humalog). As was previously reported in the topline results, BioChaperone Lispro administration produced a 61% reduction in two-hour postprandial glucose excursions (as measured by glucose area under the curve, p<0.0001) compared to Humalog. BioChaperone Lispro also reduced 30-minute postprandial excursions by 51% (p=0.0004), one-hour excursions by 58% (p<0.0001), three-hour excursions by 75% (p=0.0002), and eight-hour excursions by 42% (p=0.04). In terms of blood glucose concentration, BioChaperone Lispro led to a 73% reduction in one-hour post-meal blood glucose concentration (p<0.0001) and a 67% reduction in two-hour blood glucose concentration (p=0.0014). Peak blood glucose was reduced by 24% with BioChaperone Lispro administration compared to Humalog (p=0.016). Hypoglycemia rates were comparable between the BioChaperone Lispro and Humalog groups, with 18 events with BioChaperone Lispro and 19 events with Humalog. Adverse events were similar between the two groups as well; infection and headache were the most frequent adverse events and there were no severe adverse events in either group.

• BioChaperone Lispro uses Adocia’s proprietary carrier technology, resulting in a faster-on, faster-off profile. BioChaperone Lispro reached its half-maximal concentration 37% faster than Humalog (in 18 min, compared to 29 min for Humalog). BioChaperone Lispro also achieved a 168% higher insulin exposure vs. Humalog in the first 30 minutes post-administration (p<0.0001) and a 52% higher insulin exposure in the first hour post-administration. Post-peak, BioChaperone Lispro concentration also declined 15% more rapidly than Humalog: the candidate reached its half-maximal concentration in 135 min post-administration, compared to 160 min for Humalog. Eight-hour insulin exposure, as measured by area under the curve, was 21% lower with BioChaperone Lispro. Overall, BioChaperone Lispro achieved its maximum concentration 25% faster than Humalog (after 47 min vs. 62 min) and its maximum concentration was 13% higher than Humalog (117 mU/l vs. 104 mU/l). Overall exposure was similar between the two insulins, however. These results are consistent with previous studies.
• In Q&A, Dr. Heise suggested that the faster absorption rate of BioChaperone Lispro could support more flexible dose timing in addition to improved postprandial control. He especially sees potential for the use of BioChaperone Lispro and other ultra-rapid-acting insulins in children or elderly patients. There has been some hope that MannKind’s inhaled insulin Afrezza could serve as a convenient mealtime insulin with a more rapid absorption profile, but uptake as been sluggish due to a combination of complicated prescribing requirements and potential safety concerns - we strongly believe both barriers can and should be mitigated. The “next-generation” rapid-acting insulin analog field has not progressed as rapidly as the basal insulin analog field (where Novo Nordisk’s Tresiba [insulin degludec] has been characterized as a near-perfect basal insulin in terms of PK/PD profile), but we’re energized by the positive data that’s emerging surrounding BioChaperone Lispro and Novo Nordisk’s faster-acting insulin aspart.

Nocturnal Glycemic Control with Glargine Titration Based on Bedtime in Addition to Fasting Plasma Glucose in Type 1 Diabetes

Francesca Porcellati, MD, PhD (University of Perugia, Italy)

Dr. Francesca Porcellati presented study findings showing the benefits of an insulin titration algorithm based on the relationship between nocturnal plasma glucose (PG) and next morning fasting plasma glucose (FPG) levels. In this study, 58 participants with type 1 diabetes on basal-bolus therapy and FPG >130 mg/dl were randomized to algorithm #1 (the usual glargine titration based on FPG of six days) or algorithm #2 (based on the difference between bedtime PG and next morning FPG on days with post-dinner PG at the target 100-130 mg/dl with optimized evening prandial insulin) for three months. At three months, fasting plasma glucose decreased with both algorithms, but more so with algorithm #2 (154±17 mg/dl to 140±16 mg/dl vs. 151±18 mg/dl to 128±8 mg/dl, p<0.05). In addition, both intra-subject variability of FPG (CV 9±1.4% vs. 15±2.7%, p<0.05) and incidence of nocturnal confirmed hypoglycemia (5.4±1.4 vs, 7.6±2.7 events/patient-year) were lower on algorithm #2 compared to algorithm #1. Thus, Dr. Porcellati concluded that using an algorithm that incorporates bedtime PG may bring about several advantages in glycemic control, hypoglycemia risk, and A1c.

Questions and Answers

Q: We’re driven to overbasalize patients, largely because pharma companies have basal insulins. Why not also use this in type 2 diabetes?

A: In type 2, it’s different because if you use basal insulin, you are really following fasting. But I partly agree – for some of our patients with basal insulin, it’s important to check bedtime glucose.

Q: From my experience, I can recommend you to expect differences in type 1 diabetes. That’s why we are free to titrate basal first. The difference between bedtime and morning glucose levels is important. A three-point profile is quite simple.

A: We need to move attention more to postprandial control, which is tough to ask from patients.

Oral Presentations: Treatment and Management of Complications – Can a Dog Really Smell Hypoglycemia?

Glycemic Control and Hypoglycemia Benefits with Insulin Glargine 300 U/mL (Gla-300) Extend to People with Type 2 Diabetes (T2DM) and Mild-to-Moderate Renal Impairment

Javier Escalada MD, PhD (Clinica Universidad de Navarra, Spain)

Dr. Escalada presented a post-hoc meta-analysis of the EDITION 1, 2, and 3 trials that compared the effects of glargine 300U/ml (Gla-300) and glargine 100U/ml (Gla-100) on A1c reduction and hypoglycemia in type 2 diabetes patients with renal impairment. The meta-analysis included patients with moderate (GFR ≥30 to 60; n=401) or mild renal impairment (GFR ≥60 to 90; n=1,390), and those with normal renal function (GFR ≥90; n=685). Those with severe impairment (GFR <30) were excluded due to low numbers, and Dr. Escalada noted that this was a drawback to the meta-analysis. In reviewing the rationale for this analysis, Dr. Escalada stated that renal impairment increases the risk of hypoglycemia in type 2 patients, and thus may limit treatment options. Across all three subgroups, at six months, Gla-300 and Gla-100 provided similar reductions in A1c, and the percentage of patients who achieved an A1c of <7% and <7.5% was similar between the two drug doses. Of note, regardless of renal function, Gla-300 led to a lower rate of confirmed (≤70 mg/dl) or severe nocturnal hypoglycemia (rate ratio of 0.59 [95% CI: 0.39-0.90], 0.72 [0.56-0.93], and 0.69 [0.43-1.10] for the moderate, mild, normal groups, respectively), with comparable or lower rates of any-time hypoglycemic events.

• In opening, Dr. Escalada cited the results of EDITION 1, 2, and 3 – multicenter, randomized, open-label, phase 3a studies where patients received once daily injections of glargine 300U/ml or glargine 100U/ml titrated to a fasting SMPG of 80-100 mg/dl.  EDITION 1 enrolled patients on basal and prandial insulin with or without metformin; EDITION 2 recruited patients on basal insulin and oral therapy; and EDITION 3 enrolled insulin-naïve patients taking oral therapy. The six-month data from these studies showed that in patients with type 2 diabetes, Gla-300 provided comparable glycemic control with less hypoglycemia compared to Gla-100. Post-hoc analyses have shown that these benefits persisted when controlling for age, BMI, and duration of diabetes.
• Regarding baseline characteristics, the three groups had comparable gender balance (% male 48-54) and BMI (34-35 kg/m²). Those with moderate renal impairment were older (average age of 65 vs. 59 for mild impairment and 52-53 for normal renal function). These participants also had a longer duration of diabetes (15 years vs. 12 for mild impairment and 10 for normal renal function), as well as a longer duration of basal insulin use (5.7-6.0 vs. 5.4-5.5 for mild impairment and 4.1-4.3 for normal renal function).
• Glargine 300 U/ml and 100U/ml provided comparable A1c reductions, a finding observed in all three subgroups (Table 1). The percentage of patients that achieved an A1c of <7% and <7.5% was similar between the two drug doses, and this result was also observed across all three subgroups (Table 2).

Table 1: A1c reductions observed with Glargine 300 U/ml vs. Glargine 100U/ml

Table 2: Percentage of patients that achieved an A1c of <7% and <7.5%

Table 3: Participants with at least one event of hypoglycemia

Questions and Answers

Q: While the relative benefit of glargine 300 is clear, one of the questions was whether there were indeed more hypoglycemic episodes in the group with decreased renal function. It was a little difficult to tell that from the slides.

A: [Dr. Escalada referred to a slide with Table 3 (shown above)]. You can see here that patients with the worse renal function had a higher percentage of patients suffering from severe hypoglycemia. So you are right that in this case, the hypoglycemia burden was higher in patients with lower eGFR.

Oral Presentations: Management of Hyperglycemia in the Hospitalized Patient (with State-of-the-Art Lecture)

Efficacy and Safety of U500 Insulin Use in Hospitalized Patients at VA Pittsburgh Health Care System (VAPHS)

Ha Nguyen, MD (University of Pittsburgh Medical Center, PA)

Dr. Ha Nguyen shared data from a retrospective chart review of 90 hospitalizations of patients on outpatient U500 insulin between 2000-2015. Dr. Nguyen shared that U500 is a concentrated human insulin that is often the best option in markedly insulin resistant diabetes, but noted that it can have deleterious side effects. Accordingly, 44 patients switched to U100 during their hospital stays, while 46 remained on U500. There was no significant difference between the two groups in mean blood glucose level or incidence of hypoglycemia, indicating that U500 insulin therapy is indeed safe in the hospital setting. However, given its inherent risks, Dr. Nguyen emphasized that U500 should be administered under the supervision of an endocrinologist and with prefilled syringes to minimize dosing errors.

Questions and Answers

Q: A recent study found that a group of patients on U500 insulin had more hyperglycemia and hypoglycemia than a group on U100 insulin; why do you think your study found different results?

A: I saw that study, actually. We believe this discrepancy is because, in that study, only 60% of patients had endocrine consult – that could be why U500 had more hyperglycemia and hypoglycemia. In our study, 95% had endocrine consult.

Posters

SWITCH 1: Reduced Hypoglycemia with Insulin Degludec (IDeg) vs. Insulin Glargine (IGlar), Both U100, in Patients with T1D at High Risk of Hypoglycemia: A Randomized, Double-Blind, Crossover Trial (87-LB)

T Bailey, G Gerety, J Gumprecht, A Philis-Tsimikas, C Hansen, T Nielsen, and M Warren

SWITCH 1 demonstrated significant hypoglycemia reductions with Tresiba vs. Lantus in patients with type 1 diabetes at high risk for hypoglycemia. The double-blind trial randomized 501 patients to receive once-daily doses of Tresiba or Lantus for 32 weeks, followed by crossover to the other treatment for 32 weeks. Each 32-week period consisted of a 16-week titration period and a 16-week maintenance period, and both groups received injections of NovoLog (insulin aspart) at mealtime. Results showed a significant 11% reduction for the primary endpoint of severe or blood glucose-confirmed symptomatic hypoglycemia with Tresiba vs. Lantus during the maintenance period (event rates of 2,220.9 vs. 2,462.7 events/100 patient-years; p<0.0001). Tresiba also produced a significant 36% reduction in severe or blood glucose-confirmed nocturnal symptomatic hypoglycemia (event rates of 277.1 vs. 428.6 events/100 patient-years; p<0.0001) and a significant 35% reduction in severe hypoglycemia (event rates of 69.1 vs. 92.2 events/100 patient-years; p<0.05) in the maintenance period compared to Lantus. Results were similar for the full treatment period with significant reductions of 6%, 25%, and 26% with Tresiba vs. Lantus for the three respective endpoints. The results for other efficacy and safety parameters were comparable between groups; a post-hoc analysis found a 3% significantly lower total daily insulin dose in the Tresiba group.

SWITCH 2: Reduced Hypoglycemia with Insulin Degludec (IDeg) vs. Insulin Glargine (IGlar), Both U100, in Patients with T2D at High Risk of Hypoglycemia: A Randomized, Double-Blind, Crossover Trial (90-LB)

A Bhargava, LB Chaykin, R De La Rosa, Y Handelsman, L Troelsen, K Kvist, and P Norwood

SWITCH 2 demonstrated significant hypoglycemia reductions with Tresiba vs. Lantus in patients with type 2 diabetes at high risk for hypoglycemia. The double-blind trial randomized 721 patients to receive once-daily doses of Tresiba or Lantus in addition to oral diabetes drugs (excluding sulfonylureas/meglitinides) for 32 weeks, followed by crossover to the other treatment for 32 weeks, with the same titration/maintenance periods as in SWITCH 1. Results showed a significant 30% reduction in severe or blood glucose-confirmed symptomatic hypoglycemia with Tresiba vs. Lantus during the maintenance period (event rates of 185.6 vs. 265.4 events/100 patient-years; p<0.0001). Tresiba also produced a significant 42% reduction in severe or blood glucose-confirmed nocturnal symptomatic hypoglycemia (event rates of 55.2 vs. 93.6 events/100 patient-years; p<0.0001). Rates of severe hypoglycemia were low in both groups and numerically but not significantly lower with Tresiba (event rates of 5.3 vs. 9.1 events/100 patient-years; p-value not given). Results were similar for the full treatment period with significant reductions of 23% and 25%, respectively, for the first two endpoints and a 51% reduction in severe hypoglycemia that just reached statistical significance (p=0.03). The results for other efficacy and safety parameters were comparable between groups; a post-hoc analysis found a 4% significantly lower insulin dose in the Tresiba group.

Similar Glucose Control, Postprandial Glucose Excursions, and Safety in People with T1DM Using SAR342434 or Insulin Lispro in Combination with Insulin Glargine (Gla-100): SORELLLa 1 Study (94-LB)

SK Garg, K Wernicke-Panten, M Rojeski, S Pierre, and K Jedynasty

This poster featured initial phase 3 data demonstrating the non-inferiority of Sanofi’s SAR342434 to Lilly’s Humalog (U100 insulin lispro), in combination with insulin glargine. Developed as a rapid acting follow-on product to Humalog, SAR has an identical amino acid sequence to that of LIS and a previous clamp study determined that SAR was similar in pharmacokinetic exposure and pharmacodynamics activity to LIS. This phase 3 study – entitled SORELLA 1 – randomized 507 type 1 patients to either a multiple daily injection regimen of SAR or LIS in addition to once-daily GLA-100. At 26 weeks, the SAR and LIS groups achieved A1c reductions of 0.42% and 0.47%, respectively, with a LS mean difference of 0.06%. In addition, both groups showed similar post-prandial glucose excursions and insulin dosages. Almost all patients reported at least one episode of hypoglycemia, and a similar percentage of SAR- and LIS-treated patients reported hypoglycemia or severe hypoglycemia difference. In both SAR- and LIS- treated patients, anti-insulin lispro antibody incidence levels were similar (59.1% vs. 59.5% respectively). Each treatment group had one patient who discontinued treatment due to a treatment-emergent adverse event: 42.9% of SAR-treated and 41.7% of LIS-treated reported any adverse event. One death was reported in the SAR group due to a cardiovascular event not considered to associated with either hypoglycemia or the experimental treatment. In addition, both SAR-treated and LIS-treated patients reported similar weight gains of .69 kg and .67 kg, respectively. Thus, the study’s findings concluded that SAR was just as effective and well-tolerated as insulin lispro in people with type 1 diabetes.

Efficacy and Safety of LixiLan vs. Insulin Glargine According to Baseline Characteristics in Patients with Type 2 Diabetes from the Lixilan-L Trial (1018-P)

C Wysham, R Bonadonna, V Aroda, MP Domingo, C Kapitza, W Stager, C Yu, E Niemoeller, E Souhami, and R Bergenstal

This analysis from the LixiLan-L trial demonstrated consistent efficacy and safety with Sanofi’s iGlarLixi (formerly LixiLan; insulin glargine/lixisenatide) across subgroups divided by baseline A1c, diabetes duration, and BMI. Primary results from the trial presented as an oral presentation demonstrated superior glycemic control with iGlarLixi vs. insulin glargine (Lantus) in patients not at goal on basal insulin. In this analysis, participants were divided into groups based on their baseline A1c (<8% or ≥8%), time since diagnosis of type 2 diabetes (<10 or ≥10 years), and BMI (<30 or ≥30kg/m²). After 30 weeks, the results for A1c reduction, percentage of patients with an A1c <7%, and hypoglycemia were consistent across all subgroups. iGlarLixi consistently led to ~0.5% greater A1c reductions and ~20-30% more patients achieving an A1c <7% compared to insulin glargine, and there were no significant differences in hypoglycemia between treatment groups. iGlarLixi also offered a significant weight benefit vs. insulin glargine in subgroups divided by baseline A1c and BMI (results for duration of diabetes subgroups not given. See the table below for detailed results. 

Efficacy and Safety of MK-1293 Insulin Glargine Compared with Originator Insulin Glargine (Lantus) in Type 2 Diabetes (T2D) (926-P)

P Hollander, G Golm, W Carofano, R Eldor, M Crutchlow, M Marcos, M Rendell, P Home, B Gallwitz, and J Rosenstock

Merck’s Samsung-partnered biosimilar insulin glargine candidate MK-1293 demonstrated similar efficacy and safety to Sanofi’s Lantus in people with type 2 diabetes over 24 weeks. In this phase 3, active-controlled, open-label trial, people with type 2 diabetes (A1c ≤11%) were randomized 1:1 to once-daily MK-1293 (n=265) or Lantus (n=266), guided by a fasting glucose-based dosing algorithm, and with oral agents and prandial insulin continued. At 24 weeks, from a baseline A1c of ~8.3%, the MK-1293 and Lantus groups achieved A1c reductions of 1.28% and 1.30%, respectively, with a difference of 0.03%, meeting the non-inferiority and equivalence criteria. In addition, the two groups had very similar insulin doses: the MK-1293 and Lantus groups had basal doses of 48.3 U/day and 46.9 U/day, respectively. On safety, both groups also had similar anti-insulin antibody (AIA) responses and the study showed no clinically meaningful between-group differences in the reported adverse events including symptomatic hypoglycemia, injection site reaction, systemic allergic reaction, anaphylactic response, and angioedema. As background, Merck recently shared that MK-1293 is filed in Europe, with expectations of data being released this year (data from the phase 3 trial in type 1 diabetes was presented by Dr. Philip Home at this meeting – see above). MK-1293 is one of the first three insulin glargine biosimilars (the other two being from Lilly/BI and Biocon/Mylan) and while we have not explicitly heard plans for a US filing, we would expect one to come soon alongside Europe’s. For more on these latest developments, please read our coverage of Merck’s 1Q16 update.

IDegLira is Efficacious Across Baseline HbA_1c Categories in Subjects With Type 2 Diabetes Uncontrolled on SU, GLP-1RA or Insulin Glargine: Analyses From Completed Phase 3b Trials (925-P)

C Sorli, S Harris, E Jódar, I Lingvay, K Chandarana, J Langer, and E Jaeckel

Novo Nordisk presented a post hoc analysis of the phase 3b DUAL trials for GLP-1 agonist/basal insulin combination IDegLira (Xultophy; insulin degludec/liraglutide), showing that the drug’s efficacy was consistent regardless of baseline A1c. The analysis included populations uncontrolled on a GLP-1 agonist (DUAL III; IDegLira vs. continued GLP-1 agonist therapy), a sulfonylurea (DUAL IV; IDegLira vs. placebo) and insulin glargine (DUAL V; IDegLira vs. continued insulin glargine therapy). Patients in each trial were split into three different baseline A1c categories: ≤7.5%, >7.5-≤8.5% and >8.5%. In all categories, IDegLira led to significantly greater A1c reductions than the comparator therapy; as expected, the greatest reductions occurred in the highest baseline A1c category. See the table below for detailed results. Perhaps most impressively, IDegLira led to a mean final A1c <7% in all categories, underscoring its status as one of the most efficacious and versatile type 2 diabetes drugs available.

Table: A1c Reductions Across Baseline A1c Categories in the DUAL Trials

P=0.004 for DUAL III baseline A1c ≥8.5%; p<0.001 for all other categories

Impact of Baseline HbA1c, BMI, and Diabetes Duration on the Efficacy and Safety of LixiLan (Insulin Glargine/Lixisenatide Titratable Fixed-Ratio Combination) vs. Insulin Glargine and Lixisenatide in the LixiLan-O Trial (1028-P)

M Davies, L Leiter, G Grunberger, FJ Ampudia-Basco, B Guerci, C Yu, W Stager, E Niemoeller, E Souhami, and J Rosenstock

This analysis of the LixiLan-O trial demonstrated consistent efficacy and safety with Sanofi’s iGlarLixi (formerly LixiLan; lixisenatide/insulin glargine) across subgroups divided by baseline A1c, diabetes duration, and BMI. Primary results presented as an oral presentation demonstrated superior glycemic control with iGlarLixi vs. either component alone in patients with type 2 diabetes not at goal on oral medications. In this analysis, participants were separated into groups by baseline A1c (<8% or ≥8%), duration of type 2 diabetes (<7 or ≥7 years) and BMI (<30 or ≥30 kg/m²). After 30 weeks, the results for A1c reductions, the percentage of patients with an A1c <7%, and hypoglycemia were consistent across all subgroups. iGlarLixi consistently led to significantly greater A1c reductions (~0.3% vs. insulin glargine and 0.7%-0.9% vs. lixisenatide) and more patients achieving an A1c <7% compared to both components; hypoglycemia was comparable between the iGlarLixi and insulin glargine groups. See the table below for detailed results.

Consistent Outcomes Across Dose Ranges With Titratable LixiLan, Insulin Glargine/Lixisenatide Fixed-Ratio Combination, in the LixiLan-O Trial (1017-P)

R Henry, B Ahrén, M Davies, Y Wu, Y Handelsman, E Souhami, E Niemoeller, and J Rosenstock

Sanofi presented data from the LixiLan-O trial showing that iGlarLixi (formerly LixiLan; lixisenatide/insulin glargine) was consistently safe and effective and produced minimal weight gain across all dose ranges. Primary results from the trial presented as an oral presentation demonstrated superior glycemic control with iGlarLixi vs. either component alone in patients with type 2 diabetes not at goal on oral medications. During the trial, the dose of insulin glargine (Lantus) was titrated weekly in both the iGlarLixi and insulin glargine groups to a fasting plasma glucose target of 80-100 mg/dl, with a cap of 60 U/day (the maximum dose available in the combination). In the iGlarLixi group, two different pens with different insulin glargine/lixisenatide fixed ratios were used depending on the required dose of insulin glargine. Patients requiring 10-40 U/day of insulin glargine were treated with the lower-dose pen (ratio of 2 U insulin glargine/1µg lixisenatide), while those requiring insulin glargine doses of 30-60 U/day were treated with the higher-dose pen (ratio of 3 U insulin glargine/1 µg lixisenatide). In this analysis, patients in the iGlarLixi group were divided into subgroups based on their final doses of insulin glargine (≤10-<20 U, ≥20-30 U, ≥30-≤40 U, and >40-≤60) and lixisenatide (≥5-<10 µg, ≥10-<15 µg, and ≥15-≤20 µg). A1c reductions, the percentage of patients achieving an A1c <7%, and the incidence of hypoglycemia in the iGlarLixi group were consistent across all dose categories, and the weight gain seen with insulin glargine alone was mitigated with all doses of iGlarLixi. The incidence of nausea/vomiting was low, which the authors attributed to the gradual titration of lixisenatide.

Symposium: The New Face of Injectable Options

Benefits and Limitations of Concentrated Insulin

Wendy Lane, MD (Mountain Diabetes and Endocrine Center, Asheville, NC)

Concentrated insulin guru Dr. Wendy Lane took to the podium to discuss the newly expanded range of concentrated insulins available to clinicians and patients. We appreciated the nuance in how Dr. Lane described the strengths and weaknesses of new concentrated basal analogs Toujeo (insulin glargine U300) and Tresiba (insulin degludec) U200, relative to the reigning heavyweight Humulin U500, Lilly’s concentrated human insulin formulation. Dr. Lane seemed to favor slightly more things about Tresiba U200, namely that: (i) its pen holds more units than the Toujeo pen (also meaning fewer copays); (ii) its duration of action is the “longest of any basal insulin;” (iii) bioequivalence with Tresiba U100 means no need for dose titration with the switch to U200, whereas you need to up-titrate in the switch from insulin glargine U100 (Lantus) to U300 (Toujeo). Despite the differences, she was positive on both new insulins when used appropriately. Later at a corporate symposium on concentrated insulins, Dr. Lane shared that she is using Humulin U500 less often following the introduction of Toujeo and Tresiba U200. For more on this topic, see our coverage of her discussion on this topic at this past year’s ENDO.

• Dr. Lane is optimistic about the potential for concentrated rapid-acting analogs like Humalog (insulin lispro) U200 in pumps. Even Humulin U500 – an imperfect insulin for use in a pump – has demonstrated efficacy in pumps in patients with very high daily insulin needs. Dr. Lane pragmatically pointed out that part of the advantage of a more concentrated rapid-acting insulin would be fewer cartridge replacements and fewer copays.
• For those not familiar with the world of concentrated insulin formulations, the benefits are real, and include: (i) improved absorption from smaller-volume insulin depots, leading to more predictable insulin action; (ii) fewer injections and/or lower volume per injection to enhance patient comfort, potentially with a positive effect on compliance; and (iii) in some cases (such as insulin glargine), concentrating insulin can prolong its action profile.

Questions and Answers:

Q: In my view, Humulin U500 is not a bolus insulin anymore, and it’s too slow to put in a pump. The advantage of concentrated insulin is to flatten the PK profile for longer duration.

A: What you’re saying makes sense if you’re looking at the PK profile, but if you put it into a pump, you change its behavior somewhat. I’ve found that it works well in high dose users – it has a good postprandial effect. The problem is that patients need to bolus ahead of meals. Right now, it’s being studied in a clinical trial as MDI monotherapy, because it has both basal and prandial characteristics. In our clinical experience in several hundred patients, if you put U500 into a pump in a high dose insulin user, you get good results.

Q: There is a big risk of dosing errors for insulin in inpatient settings. Should we be saying no to concentrated insulins in-house for safety reasons?

A: For safety reasons, it’s probably best to use a U100 insulin for inpatient use.

Q: Is there strong evidence that concentrated insulins have better absorption?

A: There is not strong evidence – it’s clinical evidence, and to some degree, speculation. When you inject a high dose of U100 insulin, especially glargine, you’re going to see a point of titration that doesn’t give you a better effect. It’s either a decrease in absorption, or some sort of decreased activity either due to high volume or insulin-ase causing some sort of degradation. There is at least one paper published indicating that when you start to titrate above 0.5 U/kg, you start to lose benefit.

Swallowing Your Biologics and Not Your Pride

Chandra Sharma, PhD (Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, India)

Dr. Chandra Sharma discussed the theoretical advantages of oral insulin (better compliance, more physiological delivery of insulin to the liver) before discussing his own research group’s work on oral insulin technology. His group’s investigational platform involves a pH-sensitive polymer of layered nanoparticles that can be absorbed across the intestinal mucosa. According to his group’s preclinical studies, 93% of the particles are less than 100nm in size, and a 30-45 U/kg dose in a diabetic rat model yielded maximum glucose level reductions of 50%-70% with bioavailability of 22%-24%. We don’t have much to compare this to as we haven’t seen much equivalent data on other investigational oral insulin delivery systems (much of which, presumably, is proprietary), but it’s exciting to see all the progress being made on the challenging task of oral peptide delivery.

Smart Insulins and Nanotechnology for Diabetes Management – Reality or Myth?

Daniel Anderson, PhD (MIT, Cambridge, MA)

Dr. Daniel Anderson’s fascinating talk covered a range of topics at the forefront of smart insulin. He opened by discussing three approaches to modifying the insulin structure and imparting glucose-responsive behavior: binding of insulin to endogenous targets such as albumin and lectin (which would then be displaced by glucose, freeing the insulin molecule), changing the solubility or aggregation of insulin in a glucose-dependent way, and developing an insulin that relies on glucose to bind to its receptor. Dr. Anderson then highlighted the potential to package insulin molecules into “smart” microspheres. He shared that his lab has constructed a microgel that swells and enlarges its pores in response to glucose, thereby providing a potential glucose-dependent mechanism of insulin release. Notably, Dr. Anderson also considered the possibility of using nanoparticles to alter gene expression and cure rare genetic forms of diabetes. In concluding his presentation, Dr. Anderson turned to a different topic of interest – using new biomaterials to make capsules that can promote and protect transplanted islet cells in their new human host.

• Dr. Anderson covered three types of covalent modifications to the insulin structure that could impart glucose-responsive behavior. First, experiments dating back to 1979 have investigated the use of insulin bound to endogenous targets such as lectin and albumin. Glucose can disrupt such binding, leading to release of free insulin. The technology led to the foundation of the company SmartCells, which was acquired by Merck in 2010. Dr. Anderson expressed excitement as he remarked that several clinical trials on this technology are currently ongoing – see our Merck 1Q16 report for the latest on the company’s smart insulin candidate MK-2460. Secondly, Dr. Anderson’s lab has focused on conjugating insulin to phenylboronic acid (PBA), a compound that can reversibly bind glucose. Binding of glucose to the PBA-insulin complex can alter the charge on insulin, thus influencing its availability. Dr. Anderson’s team has already developed several forms of a PBA-detemir complex, which has performed better than both native insulin and detemir in mouse studies. Lastly, Dr. Anderson commented that glucose-dependent binding of insulin to its receptor is a third promising mechanism for smart insulin.
• Dr. Anderson then discussed the potential to package insulin molecules into smart microspheres that respond to glucose – either by breaking down or by swelling up and enlarging their pores. Dr. Anderson highlighted the need for rational design of biomaterials, noting that the sugar polymers found in biodegradable sutures have also been used to make the microcapsules that work in exenatide. A next would be to use such capsules not just for sustained release (as in the case of exenatide), but for glucose-responsive release. Dr. Anderson cited an example from his lab, which has used glucose oxidase to construct microgels that swell in response to glucose, and that are biodegradable.
• Dr. Anderson remarked that despite current advances in technology, significant challenges lie ahead in order to make a smart insulin that meets the requirements – i.e., rapid on/off, no dose dumping, biocompatibility, antigenicity, and clearance of the encapsulating materials.
• Dr. Anderson posited whether nanoparticles could be used to correct genetic elements, and thus potentially cure the very rare forms of diabetes that are based on single gene mutations. He noted that nanoparticles have already been used to deliver siRNA into cells (to inhibit gene expression in certain types of liver disease) and to bring mRNA into cells (to promote specific protein production).
• In concluding his talk, Dr. Anderson turned to islet transplantation, noting that new materials can be used to make the capsules that hold transplanted islet cells in the host body. These capsules must allow for the delivery of nutrients and oxygen to the islet cells, permit transport of insulin out of the capsule, and avoid the host immune system. His lab has used analogs of alginate (a compound derived for seaweed) to create such capsules, which so far have been shown to keep islet cells alive for up to four months.

Questions and Answers

Q: This is fascinating. I have a basic question – is there shared technology between the production of nanoparticles and biosimilar drugs?

A: No; each is customizable for its application.

Q: One of your former post-docs has received a JDRF award looking at smart patches. Can you share some information about those?

A: The vision is that patients could have a painless patch. The microneedles in the patch would provide delivery, but would not hurt because they aren’t deep enough. And you can have a patch that provides not only delivery, but smart delivery.

Inhaled Insulin – Where are we Going From Here?

Stefano Del Prato, MD (University of Pisa, Pisa, Italy)

Dr. Stefano Del Prato offered a fairly negative take on inhaled insulin, arguing that clinical trials have not demonstrated clear advantages in terms of clinical outcomes or patient convenience and that more long-term data is needed to fully understand pulmonary safety. He noted that MannKind’s inhaled insulin Afrezza has demonstrated non-inferiority at best compared to injected insulin in terms of A1c reductions. He acknowledged the potential advantages on postprandial control but noted that there have not been any studies comparing inhaled insulin to other solutions like GLP-1 agonists that could provide the same benefit. For Dr. Del Prato, the biggest clinical advantage of inhaled insulin is that it may facilitate the initiation of insulin therapy among patients who would otherwise be reluctant based on data from the EXPERIENCE trial of Pfizer’s Exubera. Dr. Del Prato was fairly skeptical about the promised convenience advantages of inhaled insulin, noting that clinical trials of Afrezza did not show a significant benefit on patient-reported outcomes. In terms of safety, Dr. Del Prato believes that questions still remain about inhaled insulin’s effects on the lungs and that long-term studies are needed to evaluate the risk of lung cancer and declining pulmonary function. Dr. Del Prato received some pushback during Q&A from clinicians who have had positive experiences with Afrezza (see more below); he responded that he believes the subject is still open for discussion but that the field must rely on hard evidence from clinical trials rather than anecdotal reports.

• During Q&A, Dr. Nancy Bohannon (California Pacific Medical Center, San Francisco, CA) stated that it has taken her a year of experience to determine how to optimize inhaled insulin therapy for each of her patients. She spoke very positively about her overall experience with Afrezza but suggested that individualization of therapy requires a lot of trial and error. For example, many of her patients needed to take an extra dose of Afrezza a few hours after the first dose, and some needed to increase their basal insulin dose because they had been unknowingly relying on injected rapid-acting insulin for part of their basal coverage. If other clinicians have had similar experiences, that could help explain why Afrezza has struggled with new patient retention while still receiving very positive reviews from a subset of patients.     

Questions and Answers

Q: You said it’s not clinically advantageous, but I’ve had a number of patients who really like using this.

A: I’m not saying it can’t be used. I’m saying if you look at the data and define an advantage as an improvement in the clinical outcome of A1c, so far the data don’t suggest any specific advantage. If it can facilitate the use of insulin, that is welcome.

Q: Maybe we need a study to capture patient-reported outcomes in a better way.

A: Yes, we need to identify people gaining from this treatment.

Dr. Nancy Bohannon (California Pacific Medical Center, San Francisco, CA): A1c is only a poor reflection of control. I’ve had a really good experience with the current inhaled insulin. I believe the clinical trials were not done optimally because they didn’t know how to use it optimally. It took me a year of experience to figure out how to use it in each patient. Some need to increase the dose to the nearest next four units; others require four times as much. Many required an extra little dose at 90 minutes or three hours after the last dose. Some required an increase in basal insulin. For a standard injection of fast-acting insulin, let’s say the duration of insulin action is four to six hours. If this is gone in two hours, there’s a three-hour period there where fast-acting insulin was acting as basal insulin. On an individual basis you can often achieve much better control. In a study using the same method and the same way of administering it for every patient, we’re not seeing an improvement in A1c.

A: My point is that this is sensation and experience, not controlled trials. We need to design trials to respond to your question; otherwise we can’t conclude anything. I totally agree that we have to be smarter and come up with better ways to appreciate the potential of this treatment. I’m open to discussion but we don’t have the results.

Symposium: Inpatient Management of Diabetes and Hyperglycemia – Novel Insights and Effective Approaches

Effective Transition from IV to SQ Insulin Therapy – Best Practices and Tricks of the Trade

David Baldwin, MD (Rush University Medical Center, Chicago, IL)

Dr. Baldwin discussed the many subtle yet key considerations a physician needs to make when deciding how and when to transition a patient from intravenous (IV) to subcutaneous (SQ) insulin therapy. Readiness is determined by whether the patient is hemodynamically stable, whether they are dependent on vasopressors or epinephrine, and whether the current IV insulin requirement can realistically be mimicked with SQ insulin dosing. Particular attention also needs to be paid to whether the patient is eating regularly. Dr. Baldwin also highlighted the importance of judging transition success over the following 2-4 days rather than simply the first 24 hours, noting that many adjustments in basal/bolus doses over that time period are to be anticipated.

Corporate Symposium: A Case-based Approach to Understanding a Once-Daily Basal Insulin Option for Your Patients (Sponsored by Novo Nordisk)

Summary

Davida Kruger, MSN (Henry Ford Health System, Detroit, MI), Anne Peters, MD (USC, Los Angeles, CA), Christopher Sorli, MD, PhD (Billings Clinic, MT), Todd Hobbs, MD (North America CMO, Novo Nordisk, Plainsboro, NJ)

This star-studded, Novo Nordisk-sponsored corporate symposium featured an in-depth look at the company’s next-generation basal insulin Tresiba (insulin degludec), which was recently launched in the US. Ms Davida Kruger (Henry Ford Health System, Detroit, MI) and Drs. Anne Peters (USC, Los Angeles, CA) and Christopher Sorli (Billings Clinic, MT) spoke very highly of Tresiba’s long profile of action and, in particular, the opportunity for flexible dosing in the case of missed injections. Ms. Kruger pointed out that with other basal insulins, there is no recourse for a missed dose other than waiting until the next scheduled dose time, which often means the patient’s fasting glucose will be poorly controlled for the whole day. On the other hand, patients who miss a dose of Tresiba can inject it as soon as they remember as long as it’s at least eight hours before the next scheduled dose. Dr. Peters pointed out that the flexible dosing feature could be especially helpful for shift workers and other patients with unpredictable schedules. Dr. Peters also noted that, due to the enhanced stability of the steady state of Tresiba, her patients don’t have to adjust the dose day-to-day as some do for other basal insulins. Though Tresiba’s only been available on the US market for a few months, its clear that the product is already winning over many healthcare providers and educators with the clinical advantages offered by the product.

Product Theaters

A Treatment Option for Patients who are Severely Insulin Resistant (Sponsored by Sanofi)

Timothy Gilbert, MD (Texas Diabetes & Endocrinology, Dallas, TX) and Jeremy Pettus, MD (University of California San Diego, San Diego, CA)

Dr. Pettus asked the audience to think of Toujeo (U300 insulin glargine) as a completely new basal insulin, as it has a PK profile distinct from that of Lantus (U100 insulin glargine). He reviewed the basic characteristics of the drug, including its lower injection volume (one-third that of Lantus), the fact that it forms a smaller precipitate than Lantus, and the convenience offered by the one-to-one unit conversion between the Lantus and Toujeo pens. Both Dr. Pettus and Dr. Gilbert highlighted that Toujeo is more stable than Lantus over 24 hours. In reviewing the six-month non-inferiority phase 3 EDITION studies that compared Toujeo to Lantus, both physicians focused on EDITION 3, which recruited insulin-naïve type 2 diabetes patients uncontrolled on oral agents. They highlighted that both drugs had similar A1c reductions, and that Toujeo had improved rates of hypoglycemia. During the second half of the talk, the two physicians reviewed a patient example, walking the audience through the considerations of starting basal insulin.

• For insulin-naïve patients, Dr. Gilbert recommended starting with a Toujeo dose of 0.2U/kg/day for type 2 patients and with one-third to one-half of the total daily insulin dose for type 1 patients. For patients on once-daily long or intermediate acting insulin, he recommended a 1:1 conversion. Lastly for those on twice-daily NPH insulin, he recommended starting with 80% of the total daily NPH dose. Dr. Pettus suggested increasing the Toujeo dose every three to four days based on the patient’s personalized fasting plasma glucose target.
• In reviewing the EDITION 3 data, Dr. Pettus highlighted that both Lantus and Toujeo had similar A1c reductions, and that the rates of severe hypoglycemia and documented symptomatic hypoglycemia with Toujeo were 0.9% and 8%, respectively. Dr. Pettus acknowledged that the data for Lantus were not shown, and stated that studies have indicated a trend toward less hypoglycemia with Toujeo. That said, hypoglycemia with Toujeo has not been studied in a dedicated trial as it has with Novo Nordisk’s Tresiba (insulin degludec) in the SWITCH 1 and SWITCH 2 trials. We’ll be curious to see if Sanofi initiates a similar trial of hypoglycemia in Toujeo as it vies with Tresiba within the next-generation basal insulin market.

Options in Basal Insulin: Basaglar (Sponsored by Lilly/BI)

Tom Blevins, MD (Texas Diabetes & Endocrinology, Austin, TX)

In this Lilly/BI Saturday afternoon product theater, Dr. Tom Blevins reviewed Basaglar’s (biosimilar insulin glargine) phase 3 efficacy and safety data, highlighting its non-inferiority vs. Sanofi’s Lantus. Throughout the presentation, Dr. Blevins emphasized that while Basaglar is identical to Lantus in terms of amino acid sequence and dosing information, the FDA does not technically consider it a biosimilar – it was approved under the 505(b)(2) regulatory pathway, which will be consolidated with the newer “official” biosimilar pathway in 2020.  Dr. Blevins also commented on the delivery device – Basaglar will be delivered in a uniquely-colored KwikPen that is compatible with BD’s ultrafine needles. This is different than the delivery device for Lantus and could potentially make Basaglar more appealing for patients averse to needles. While Dr. Blevins did not comment on pricing during the presentation, he suggested during Q&A that the cost would “probably be more or less the same compared to Lantus.” We would be surprised and disappointed if this is the case given the widespread hope that biosimilar insulins can help counteract the trend toward skyrocketing insulin prices. So far, the product has been priced at about a 10%-20% discount compared to Lantus in the EU countries where it has launched. We have assumed that the discounts could be even steeper in the US given the higher list prices for basal insulin analogs there compared to Europe, though the discounts are still expected to fall well short of those for small-molecule generics. Dr. Blevins confirmed that Basaglar is expected to launch in the US launch around December 15, 2016 as per the terms of Lilly’s patent lawsuit settlement with Sanofi. During the presentation, Dr. Blevins also reviewed results from the phase 3 ELEMENT I and ELEMENT II trials (presented at ADA 2014) demonstrating non-inferiority between Basaglar and Lantus in terms of  A1c reduction and percentage of patients achieving an A1c <7% in type 1 and type 2 diabetes.

Questions and Answers

Q: Are there any differences in cost between Basaglar and Lantus?

A: The cost will probably be more or less the same. I’m not sure, as that information isn’t available yet. I would suggest continuing to communicate directly with BI and Lilly to find out exact information on pricing.

Q: Can you speak to the interchangeability in treatment with Basaglar and Lantus?

A: Basaglar did meet the criteria for non-inferiority vs. Lantus. However, I don’t believe that these two are officially interchangeable – that is not worked out. Basaglar is another option, that’s my best answer. However, there is no difference in achievement; Basaglar is non-inferior to Lantus.

A: Because Basaglar is regulated through an NDA, and interchangeability is a regulatory status, this follow-on is not deemed interchangeable in the US. We know that for sure.

Q: What does the experience of someone who is pregnant and on Basaglar look like?

A: We haven’t studied Basaglar in pregnancy.

Toujeo: A Once-daily Basal Insulin (Sponsored by Sanofi)

Bruce Bode, MD (Atlanta Diabetes Associates, Atlanta, GA), Bill Polonsky, PhD (University of California San Diego, San Diego, CA) Steven Edelman, MD (TCOYD, Del Mar, CA), Debbie Hinnen, APRN, CDE (Touro University California, Vallejo, CA)

At a relatively well-attended Sanofi product theater, Drs. Bruce Bode, Steve Edelman, Bill Polonsky, and Debbie Hinnen made a strong case for why providers should prescribe Toujeo (insulin glargine U300) in type 2 diabetes. The speakers began by taking turns presenting on Toujeo’s pharmacology, clinical data, and administration before walking through different case studies to demonstrate how to dose for a wide range of patients, from those who are insulin-naïve to those on basal-bolus therapy. Notably, the formulation was described as a particularly “forgiving” insulin, both in terms of its smooth basal rate (which allows patients to get away with errors – Dr. Bode actually noted that the flat profile is just like “what you see with an insulin pump”) and flexible dosing (which allows patients to get away with missing a morning dose). We got the sense that Toujeo fits better into patients’ lives – rather than patients having to fit their lives around the insulin – which led Dr. Edelman, in particular, to highlight the potential adherence benefits. He also acknowledged the company’s “very good” COACH program, stressing that more patient contact and support leads to better outcomes. Lastly, panelists spent time discussing the clinical transition from Lantus (insulin glargine) to Toujeo, stressing that it takes 3-4 days for the latter to achieve steady state – indeed, all the speakers had stories of patients who claimed Toujeo “didn’t work” because they did not stick with it long enough, and with that in mind, stressed that setting expectations is key.

-- by Melissa An, John Erdman, Helen Gao, Varun Iyengar, Brian Levine, Hannah Martin, Nina Ran, Emily Regier, Tony Thaweethai, Manu Venkat, Sarah Wilkins, and Kelly Close