American Diabetes Association 77th Scientific Sessions

June 9-13, 2017; San Diego, CA; Full Report – Novel Therapies – Draft

Executive Highlights

This document contains our coverage of Novel Therapies at ADA 2017. 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 2017; 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 2017 GLP-1 Agonist, DPP-4 Inhibitor, Insulin Therapy, SGLT-2 Inhibitor, and Type 1 Diabetes Cures, Adjunct Therapies, and Pathophysiology reports.

Table of Contents 

Themes

Progress on Adjunct Therapies for Type 1 Diabetes

  • In terms of novel therapies, Dr. Jeremy Pettus presented exciting phase 1 data on the last day of the conference demonstrating that a single dose of the human glucagon receptor (GCGR) antibody REMD-477 can produce substantial and long-lasting (weeks!) reductions in insulin requirements and improvements in glycemia and time-in-range in people with type 1 diabetes, without increasing hypoglycemiaIn a double-blind study, people with type 1 diabetes (n=21) were randomized to receive a single subcutaneous injection of either 70 mg REMD-477 or placebo. One day following the injection, participants who received REMD-477 experienced a significant 26% reduction (12 units) by the second day after the injection (p=0.02). Furthermore, REMD-477 produced substantial reductions in average daily blood glucose concentration not days but weeks after the injection. For people in the treatment arm, average glucose fell 27 mg/dl in the first week post-injection (p<0.0010), -31 mg/dl in the second week (p=0.05), and -20 mg/dl in the third week (p=0.05). REMD-477 further produced substantial increases in time-in-range. In the week following the injection, participants on REMD-477 spent 71% of their time in normoglycemia (70-180 mg/dl), versus 56% for those on placebo (p=0.0001), and the effect persisted into the second week post-injection (70% time-in-range with REMD-477, versus 57%; p<0.05). We are very moved by the sheer timescale of REMD-477’s powerful actions and eager to learn more about the upcoming phase 2 study, which according to Dr. Pettus will examine the effect of multiple weekly doses of the peptide drug. For good reason Dr. Pettus’ presentation was certainly one of the most highly-anticipated highlights of the President’s Oral Sessions – the very final event of ADA, highlighting particularly notable late-breaking abstracts – and we will be watching the progress of this work very closely. Although this work is clearly in its earliest stages, REMD-477 is a perfect exemplification of a patient-friendly diabetes therapy that optimizes important outcomes beyond A1c – namely time-in-range and a vastly reduced injection burden.

Advances in More Patient- and Caregiver-Friendly Glucagon for Hypoglycemia

  • Zealand and Xeris highlighted their continued progress on the liquid-stable glucagon autoinjector front at ADA 2017. In a poster, Zealand detailed phase 2 results from a PK/PD study of its liquid-stable glucagon analog dasiglucagon in people with type 1 diabetes (n=58), demonstrating that dasiglucagon, like native glucagon, can rapidly and effectively increase blood glucose concentration following a controlled, insulin-induced hypoglycemia event in which blood glucose fell to 55 mg/dl. On the pharmacodynamic front, the three highest dasiglucagon doses used in the study (0.3 mg, 0.6 mg, and 1.0 mg) each took a median of six minutes to raise plasma glucose levels to above 70 mg/dl, versus 6 and 7 minutes for the 0.5 mg and 1.0 mg doses of native glucagon, respectively. Notably, the increase in plasma glucose was longer-lasting and more pronounced with dasiglucagon; this larger glucose excursion profile promisingly suggests that dasiglucagon may be superior to native glucagon at preventing recurrent hypoglycemia. The FDA is expected to provide guidance on dasiglucagon’s development imminently. The candidate is currently in phase 2 development both as a single-dose rescue pen (phase 3 to begin as soon as 3Q17) and as a multi-dose component of a dual hormone artificial pancreas system. We were also pleased to get a glimpse at promising efficacy/safety results for Xeris’ G-Pen Mini mini-dose glucagon for both non-severe hypoglycemia events (1068-P) and for exercise-induced hypoglycemia (67-LB). All in all, we are very pleased to see this progress toward a more patient-friendly and feasible alternative to the current very complex, error-prone native glucagon kits – a longstanding area for improvement in diabetes care. This area is certainly heating up!
  • We also heart exciting updates on the nasal glucagon front from Lilly. Dr. Elizabeth Seaquist presented positive real-world data on Lilly’s phase 3 nasal glucagon, showing that 96% of patients experiencing hypoglycemia recovered within 30 minutes following treatment and that most of the caregivers were highly satisfied with the device. The study enrolled 129 adults with type 1 diabetes, and 69 of these participants experienced a total of 157 symptomatic moderate or severe hypoglycemia events (a blood glucose of approximately <60 mg/dl or requiring assistance) during the course of the study. For 151 of these episodes (96%), a 3 mg dose of nasally-delivered glucagon met its primary endpoint of “awakening or returning to normal status” within 30 minutes, as determined by a caregiver. For five of the remaining six events, caregivers noted recovery within 45 minutes, and in four of these instances, the patient’s blood glucose was ≥70 mg/dl 30 minutes after administering nasal glucagon. A majority of caregivers, 70%, were able to deliver nasal glucagon to a patient experiencing hypoglycemia within 30 seconds, while 98% were able to do so in <2 minutes – what an exciting and much-needed improvement to the lengthy reconstitution process of existing glucagon options. The health and healtheconomic burden of hypoglycemia remains far too high, and we’re hopeful that advances like Lilly’s nasal glucagon will bring us leaps and bounds ahead in our ability to treat the complication.

Growing Focus on Diabetes-Adjacent Indications

  • Repurposing existing diabetes drugs (either alone or in combination with another agent) for diabetes-adjacent indications like obesity, NASH, and prediabetes was another notable theme this year. On the SGLT-2 inhibitor front, we heard the results of a new sub-analysis of the EMPA-REG OUTCOME trial demonstrating the efficacy of Lilly/BI’s Jardiance (empagliflozin) to reduce adiposity as well as an oral presentation offering further phase 2 data on canagliflozin/phentermine combination therapy for obesity. Two posters additionally showed promising data on AZ’s Farxiga (dapagliflozin) for prediabetes and J&J’s Invokana (canagliflozin) for improved liver metabolism in people with obesity. Additional posters examined Merck’s Januvia (sitagliptin) and the TZD pioglitazone for prediabetes. GLP-1 agonists continue to show promise for obesity in particular: we were especially impressed by a meta-analysis of the entire SUSTAIN clinical trial program showing superior and clinically meaningful reductions n body weight across all five studies, versus a range of tested comparator drugs and in a broad range of patient populations. Novo Nordisk recently shared positive phase 2 topline data for a once-daily injection of semaglutide for obesity, demonstrating impressive mean body weight reductions of nearly 14% and we’re eager to see this investigated further. Novo Nordisk has a particularly robust early- and mid-stage pipeline for obesity and we’re looking forward to the newsflow on this front at future ADA meetings.
  • There is also a great deal of activity on the novel therapy front for diabetes-adjacent therapies. GLP-1 agonist combination therapy appear to be all the rage, and we were especially intrigued by posters demonstrating the ability of GABA/GLP-1 combination therapy to prevent the onset of diabetes in animal models by promoting beta cell regeneration and the efficacy of a long-acting GLP-1/glucagon/GIP tri-agonist developed by Hanmi Pharmaceuticals. Reflecting the increasingly robust obesity drug competitive landscape, entirely novel therapies for obesity also have a strong presence at this year’s conference. Posters demonstrated impressive efficacy data for early drug candidates such as Janssen’s oxyntomodulin agonist XTEN and ProMetic’s anti-fibrotic compounds PBI-4547 and PBI-4050 for obesity. On the NASH front, we saw impressive preclinical data for PB-718 from a group in Suzhou, China, as well as Spitfire Pharma’s SP-1373.

ADA Pathway to Stop Diabetes Symposium

  • As always, the ADA Pathway to Stop Diabetes symposium offered an inspiring glimpse into the future of diabetes management. Most notably, UNC’s Dr. Zhen Gu, co-founder of Zenomics, a startup recently awarded $5.8 million from MicroPort Scientific Corporation, discussed a variety of smart insulin delivery approaches currently being investigated in his lab. In his view, the main challenges facing the smart insulin field today are (i) achieving a fast response comparable to normal beta cell activity; (ii) avoiding hypoglycemia; (iii) achieving ease of administration; and (iv) ensuring biocompatibility. Overall, beyond Dr. Gu’s star power, the symposium boasted an impressive range of ongoing projects, from Dr. Daniel Ceradini’s work (NYU Langone Medical Center) investigating accelerated diabetic wound closure to Dr. Kathleen Page’s results (USC) on central adiposity in childhood as an early indicator of intrauterine exposure to gestational diabetes and maternal adiposity. Other highlights included Cornell’s Dr. Praveen Sethupathy, who discussed recent findings demonstrating how a high-fat diet contributes to small intestinal morphology and physiology, and UW’s Dr. Joshua Thaler, who remarked on astrocycte and microglial inflammatory signaling as it pertains to obesity susceptibility.

Detailed Discussion and Commentary

Oral Presentations: ADA Presidents Oral Session

REMD-477, a Human Glucagon Receptor (GCGR) Antibody, Reduces Daily Insulin Requirements and Improves Glycemic Control in People with Type 1 Diabetes (T1D)

Jeremy Pettus, MD (UCSD, San Diego, CA)

Dr. Jeremy Pettus presented exciting phase 1 data demonstrating that a single dose of the human glucagon receptor (GCGR) antibody REMD-477 can produce substantial and long-lasting (weeks!) reductions in insulin requirements and improvements in glycemia and time-in-range in people with type 1 diabetes, without increasing hypoglycemia. In a double-blind study, people with type 1 diabetes (n=21) were randomized to receive a single subcutaneous injection of either 70 mg REMD-477 or placebo. One day following the injection, participants who received REMD-477 experienced a significant 21% reduction (9 units) in daily insulin dose compared to those who received placebo (p=0.02); this intensified to a 26% reduction (12 units) by the second day after the injection (p=0.02).  Furthermore, REMD-477 produced substantial reductions in average daily blood glucose concentration not days but weeks after the injection. For people in the treatment arm, average glucose fell 27 mg/dl in the first week post-injection (p<0.0010), -31 mg/dl in the second week (p=0.05), and -20 mg/dl in the third week (p=0.05). REMD-477 further produced substantial increases in time-in-range. In the week following the injection, participants on REMD-477 spent 71% of their time in normoglycemia (70-180 mg/dl), versus 56% for those on placebo (p=0.0001), and the effect persisted into the second week post-injection (70% time-in-range with REMD-477, versus 57%; p<0.05). This increased time spent in normoglycemia with REMD-477 was driven by reductions in hyperglycemia; importantly, hypoglycemia did not increase with REMD-477. Although the mechanism of action of this candidate is not yet understood, Dr. Pettus presented evidence that a single dose of REMD-477 produces long lasting elevations in plasma glucagon and GLP-1 that don’t return to baseline until 57 post-injection. Adverse events were infrequent and minor (headache, oropharyngeal pain, etc.) and did not substantially differ between the REMT-477 and placebo groups (11 vs. 10 events), indicating a good safety profile for this candidate. We are very moved by the sheer timescale of REMD-477’s powerful actions and eager to learn more about the upcoming phase 2 study, which according to Dr. Pettus will examine the effect of multiple weekly doses of the peptide drug. For good reason Dr. Pettus’ presentation was certainly one of the most highly-anticipated highlights of the President’s Oral Sessions – the very final event of ADA, highlighting particularly notable late-breaking abstracts – and we will be watching the progress of this work very closely. Although this work is clearly in its earliest stages, REMD-477 is a perfect exemplification of a patient-friendly diabetes therapy that optimizes important outcomes beyond A1c – namely time-in-range and a vastly reduced injection burden.

Oral Presentations: New Insights into Prevention and Treatment of Hypoglycemia

Nasal Glucagon for the Treatment of Moderate-to-Severe Hypoglycemic Episodes in Real-World Settings in Adults with Type 1 Diabetes

Elizabeth Seaquist, MD (University of Minnesota, Minneapolis, MN)

Dr. Elizabeth Seaquist presented positive real-world data on Lilly’s phase 3 nasal glucagon, showing that 96% of patients experiencing hypoglycemia recovered within 30 minutes following treatment and that most of the caregivers were highly satisfied with the device. The study enrolled 129 adults with type 1 diabetes, and 69 of these participants experienced a total of 157 symptomatic moderate or severe hypoglycemia events (a blood glucose of approximately <60 mg/dl or requiring assistance) during the course of the study. For 151 of these episodes (96%), a 3 mg dose of nasally-delivered glucagon met its primary endpoint of “awakening or returning to normal status” within 30 minutes, as determined by a caregiver. For five of the remaining six events, caregivers noted recovery within 45 minutes, and in four of these instances, the patient’s blood glucose was ≥70 mg/dl 30 minutes after administering nasal glucagon. These are impressive results in a real-world setting, confirming what Locemia showed in phase 3 RCTs (Lilly acquired this pipeline product from Locemia in October 2015). A majority of caregivers, 70%, were able to deliver nasal glucagon to a patient experiencing hypoglycemia within 30 seconds, while 98% were able to do so in <2 minutes – what an exciting and much-needed improvement to the lengthy reconstitution process of existing glucagon options. Overall, 94% of caregivers were satisfied with nasal glucagon, including 56% giving it the highest “very satisfied” score. Dr. Seaquist emphasized that no calls to emergency services were made for any of the 157 hypoglycemia episodes, not even for 12 cases of severe hypoglycemia when patients were unconscious or experiencing convulsions or mental disorientation. Impressively, nasal glucagon met the study’s primary endpoint of recovery within 30 minutes in all 12 of these cases as well (experienced by seven participants), which supports the agent’s ability to rapidly raise dangerously low blood glucose in real-world settings. Though an FDA submission has taken longer than we expected since Lilly acquired the phase 3 product from Locemia (due to additional development work and establishing a manufacturing infrastructure), management shared in a separate interview with us that a filing is expected in 1H18, and the product will be submitted in other geographies shortly thereafter. The health and healtheconomic burden of hypoglycemia remains far too high, and we’re hopeful that advances like Lilly’s nasal glucagon will bring us leaps and bounds ahead in our ability to treat the complication. To that end, it’s extremely valuable to see real-world efficacy and feasibility data, since the immediate goal is to help patients/caregivers address hypoglycemia swiftly in everyday settings, avoiding an expensive hospital visit, emergency call, or need for a healthcare professional.

  • During a separate call with Dr. Seaquist and Lilly’s nasal glucagon team, we heard anecdotal evidence on caregiver responses to this innovative product: “it just makes so much sense to them.” Certainly, this intuitive ease of use is crucial for a product like glucagon, used often in high-stress emergency situations. Once nasal glucagon is available, we’ll be fascinated to see how the ease-of-use and satisfaction compares to upcoming auto-injectors in development (Xeris and Zealand, among others). 
  • According to Lilly management, the shelf life of this innovative product is anticipated to be comparable to current recombinant glucagon. We were happy to hear this, as it will be another pull for patients, providers, and payers. Cost is of course a big question with glucagon, and we so hope that this nasal glucagon is priced responsibly to maximize access to a superior, patient-friendly, cost-saving therapy. 
  • Locemia presented equally positive simulated usability data at EASD 2015, which also highlighted the simplicity of nasal delivery.

Oral Presentations: Obesity Pathogenesis and Treatment – Insights from Mouse Models

PB-718, a Dual GLP-1/Glucagon Receptor Agonist Demonstrates Superior Weight Loss Effect and Ameliorates Nonalcoholic Steatohepatitis (NASH) in Animal Models

Michael Xu, MD (Pegbio, Suzhou, China)

Dr. Michael Xu presented a range of preclinical data on an investigational, PEGylated GLP-1/glucagon receptor dual agonist – Pegbio’s PB-718. In a mouse model of diabetes (n=6), both low and high doses of the agent were associated with superior weight loss and reduced fasting plasma glucose vs. twice-daily liraglutide. In mice with NASH (n=6), both doses led to more weight loss, a greater reduction in liver weight, and a greater lowering of liver weight/body weight ratio vs. placebo (p<0.0001 for all comparisons). Moreover, there was a dose-dependent reduction in NAS score for NASH severity (p<0.01 for lower dose vs. placebo; p<0.0001 for higher dose vs. placebo), which takes into account steatosis, liver inflammation, fibrosis, and other markers. Dr. Xu also reviewed findings from a preclinical investigation of Pegbio’s drug candidate in monkeys. Consistent with the data from rodent studies, PB-718 demonstrated dose-dependent and significant superiority vs. placebo in stimulating weight loss and improving NAS score. Dr. Xu explained that there are strong mechanistic underpinnings that support the utility of GLP-1/glucagon dual agonists for diabetes, obesity, and NASH. Oxynotomodulin, an endogenous dual agonist of GLP-1/glucagon, has been correlated with decreased food intake, enhanced glucose tolerance, and improved liver health. We’re certainly excited by GLP-1/glucagon dual agonists as a potential new therapy class (competitive landscape here), and we’re happy to see companies investing in these agents for diabetes as well as adjacent indications. NASH, in particular, is a therapeutic area of high unmet need with no FDA-approved medicines to-date, and we also see marked room for improvement in available tools for obesity management.

Questions and Answers

Q: Have you compared your agent with semaglutide (Novo Nordisk’s GLP-1 agonist candidate, in phase 2 for obesity and NASH)?

A: No we have not, but we will be eager to compare our compound to semaglutide in some study. Actually, we were approached by them and tried to figure out how to compare these compounds side-by-side. Of course, semaglutide has not yet been approved.

Oral Presentations: Central Nervous System Regulation of Metabolism

Diabetes Remission Induced by Central FGF1 Is Associated with Improved Beta-Cell Function

Jenny Brown, PhD Student (University of Washington, Seattle, WA)

Ms. Jenny Brown presented data from her work in Dr. Michael Schwartz’s lab on the role of FGF1 on glucose homeostasis regulated by the brain. Dr. Schwartz’s team published an article in Nature Medicine last May demonstrating that a single intracerebroventricular (ICV) injection of FGF1 resulted in sustained remission of type 2 diabetes in mouse and rat models. The beneficial effects of central FGF1 appeared to be related to insulin secretion, as the compound was not effective in rodent models of severe insulin deficiency. Ms. Brown aimed to build on this work by answering two questions: i) Does FGF1 increase insulin secretion in animals in remission? and ii) Does diabetes remission induced by FGF1 involve other mechanisms besides increased insulin secretion? A modified hyperglycemic clamp study in rats indicated that FGF1-induced diabetes remission was associated with increased basal insulin secretion but not with increased insulin secretion in response to a glucose infusion. However, increased basal insulin secretion does not appear to be the whole story, as a modified hyperinsulinemic clamp study in rats showed that vehicle-treated animals required higher plasma insulin levels to achieve the same plasma glucose as the FGF1-treated group. It is not yet clear what the additional glucose-lowering mechanisms might be, but Ms. Brown suggested that all of these findings support a revised model of glucose homeostasis that involves a central role for the brain. We’ve been very intrigued by the work from Dr. Schwartz lab on the role of the brain in both diabetes and in obesity – our interview with him last year was absolutely fascinating and we’ve been eagerly watching closely to see what other learnings his lab may produce.

Questions and Answers

Q: Did you see the same results in female rats?

A: We haven’t tested that yet but we plan to.

Q: We just learned in an earlier talk that the dorsal vagal complex could be manipulated with a high-fat diet. Could there be an additional effect related to modulation of that complex by FGF-1?

A: We’re looking at the specific nuclei where it’s acting now.

Q: What is the source of FGF-1? Is it naturally found in those areas? What is the difference between putting it in the brain vs. the periphery?

A: When it’s given peripherally, it’s given at multiple doses. That leads to reductions in body weight and food intake. The single brain injection induces acute reductions but they’re not sustained.

Q: Did they lose their overeating behavior? Were there any other behavioral changes after a week?

A: Body weight and food intake went back to the same level as the controls. The treated animals actually weighed slightly more at the end.

Oral Presentations: Targets and Pathways in Diabetic Kidney Disease

PBI-4050 Protects against Diabetic Nephropathy and Improves Pancreatic Function in High-Fat-Diet db/db Mouse Model

Lyne Gagnon, PhD (Prometic BioSciences, Laval, Quebec, Canada)

Dr. Lyne Gagnon discussed preclinical and phase 2 data for Prometic BioSciences’ anti-fibrotic drug candidate PBI-4050. This small molecule candidate  is an agonist of an undisclosed receptor with a protective role in fibrosis and an antagonist of a second undisclosed receptor with a deleterious role in fibrosis. Data from several preclinical models have demonstrated that the compound reduces fibrosis in the lungs, kidneys, heart, and liver and has positive effects on a wide range of metabolic parameters: reduced triglycerides, increased adiponectin, decreased hyperfiltration, downregulation of inflammatory markers, increased serum insulin, and reduced liver steatosis. Dr. Gagnon reviewed results presented at AHA last November from an open-label phase 2 trial of PBI-4050 in patients with type 2 diabetes. Results demonstrated a 0.75% A1c reduction after 12 weeks among patients with a baseline A1c ≥7.5% and a 0.9% reduction among patients with a baseline A1c ≥8%. The trial also found significant reductions in several biomarkers of kidney injury and improvements in a number of biomarkers of metabolic syndrome and fibrosis. Dr. Gagnon suggested that the drug’s ability to target multiple organs (kidneys, adipose tissue, liver, pancreas, muscle) could give it an edge over existing type 2 diabetes medications. We agree that the candidate’s widespread effects and anti-fibrotic activity make it an intriguing candidate but believe that in the current environment, it will need to demonstrate a beneficial effect on cardiovascular and/or renal outcomes in order to be truly competitive. The early-stage findings are certainly suggestive, though it’s unclear if the data shared thus far would be compelling enough to encourage the massive investment of a large-scale phase 3 program in type 2 diabetes, including a CVOT.

Questions and Answers

Q: Was the gene expression data from the whole kidney or the cortex?

A: This data was from the cortex.

Q: What is the specific mechanism of action?

A: The drug acts on two receptors. I can’t say which specific ones for patent reasons.

Q: You mentioned that microparticles are reduced. What are microparticles and why are they important?

A: There was some indication that there was a reduction of microparticles from podocytes. This suggests that the compound is protecting podocytes.

Q: Do you think the anti-fibrotic effects are mainly due to FGF?

A: No, there’s regulation of many cytokines, growth factors, etc. It’s more than just FGF.

Q: Are there side effects?

A: The compound appears very safe and well tolerated. There were very few side effects. There was diarrhea in two patients. We have two more posters focused on side effects and other results, including a small but significant reduction in BMI.

Q: Was there any negative effect on wound healing or other processes that require fibrosis?

A: Good question. We saw no effect on wound healing.

Posters

Dasiglucagon, a Novel Soluble Glucagon Analog, Successfully Restores Blood Glucose Levels after Hypoglycemia in People with Type 1 Diabetes Mellitus (T1DM) (389-P)

T Heise, B Bysted, U Mouritzen, U Hovelmann, D Lamers, and D Moller

Zealand presented a poster detailing phase 2 results from a PK/PD study of its liquid-stable glucagon analog dasiglucagon. The trial compared four doses of dasiglucagon (0.1 mg, 0.3 mg, 0.6 mg, and 1.0 mg) to native glucagon (Novo Nordisk’s GlucaGen; 0.5 mg and 1.0 mg) in participants with type 1 diabetes (n=58), demonstrating that dasiglucagon, like native glucagon, was able to rapidly and effectively increase blood glucose concentration following a controlled, insulin-induced hypoglycemia event in which blood glucose fell to 55 mg/dl. On the pharmacodynamic front, the three highest dasiglucagon doses (0.3 mg, 0.6 mg, and 1.0 mg) each took a median of six minutes to raise plasma glucose levels to above 70 mg/dl, versus 6 and 7 minutes for the 0.5 mg and 1.0 mg doses of native glucagon, respectively (and 10 minutes for the 0.1 mg dasiglucagon dose). Dasiglucagon furthermore showed comparable performance to native glucagon in terms of the average time required to increase plasma glucose levels by 20 mg/dl; the four dasiglucagon doses (0.1 mg, 0.3 mg, 0.6 mg, and 1.0 mg) respectively took a median of 14, 10, 9, and 9 minutes to achieve this level of plasma glucose reduction, versus 10 minutes for both the 0.5 mg and 1.0 mg native glucagon doses. Notably, the increase in plasma glucose was longer-lasting and more pronounced with dasiglucagon: total plasma glucose excursions (as measured by area under the effect curve [AUE]) were significantly higher with 0.3 mg dasiglucagon versus 0.5 mg native glucagon (p<0.0001) and for both 0.6 mg (p=0.0043) and 1 mg (p<0.0001) dasiglucagon versus 1.0 mg native glucagon. This larger glucose excursion profile promisingly suggests that dasiglucagon may be superior to native glucagon at preventing recurrent hypoglycemia. On the pharmacokinetic front, dasiglucagon reached maximum exposure significantly later than native glucagon (~35 minutes; p<0.01), but demonstrated a significantly higher total exposure for all dose comparisons (p<0.001). In a separate conversation with Zealand, the company indicated that this could be suggestive of higher viability for dasiglucagon over native glucagon, meaning that dasiglucagon could achieve the same the same glucose increasing efficacy at lower doses – but of course this would need to be verified in future studies. Importantly, dasiglucagon was well-tolerated with a similar safety profile as native glucagon. For both dasiglucagon and native glucagon, the most commonly reported adverse events were nausea and vomiting (40 events with dasiglucagon, 35 events with native glucagon) and mild injection site reactions which disappeared within 30 minutes post-dosing (7 events with dasiglucagon, 5 events with native glucagon).

  • Following the release of these topline results in 3Q16, Zealand commented in its 4Q16 earnings update that the FDA is expected to provide guidance of dasiglucagon’s development in 1Q17. The candidate is currently in phase 2 development both as a single-dose rescue pen (phase 3 to begin as soon as 3Q17) and as a multi-dose component of a dual hormone artificial pancreas system. We are very pleased to see this progress toward a more patient-friendly and feasible alternative to the current very complex, error-prone native glucagon kits – a longstanding area for improvement in diabetes care. For more on the soluble glucagon arena more broadly, check out our soluble glucagon competitive landscape.

Mini-Dose Glucagon as a Novel Approach to Prevent Exercise-Induced Hypoglycemia in Type 1 Diabetes (67-LB)

M Rickels, S Dubose, H Wolpert, E Toschi, R Beck, M Cummins, BJ Newswanger, and MC Riddell

This phase 2 study compared Xeris’ G-Pen Mini glucagon vs. basal insulin reduction vs. glucose tabs as a way to avoid exercise-induced hypoglycemia, a persistent problem since the natural glucagon response is impaired in people with type 1 diabetes. Each trial participant (n=15) went through four conditions in a randomized crossover design: (i) control, (ii) 50% basal rate reduction five minutes prior to the start of exercise, (iii) oral glucose tabs (20 grams five minutes before start, and another 20 grams 30 minutes after start), and (iv) Xeris’ mini-dose glucagon injected subcutaneously into the abdomen five minutes prior to the start of exercise. The G-pen injection maintained plasma glucose levels between 125-175 mg/dl throughout the duration of exercise (45 minutes) and for 45 minutes after, while glucose tabs elevated blood sugar >225 mg/dl 45 minutes-post exercise. Basal insulin reduction was significantly less effective in avoiding hypoglycemia (p<0.001 vs. G-Pen), as mean plasma glucose dropped to ~75 mg/dl by the end of exercise and stayed low for 45 minutes after, which parallels almost exactly what happened on average in the control condition. In total, six people experienced hypoglycemia (defined by blood sugar <70 mg/dl) in the control condition, five in the basal rate reduction condition, and none in the mini-dose glucagon or oral tabs conditions. On the opposite end, five individuals experienced hyperglycemia (defined by blood sugar >250 mg/dl) in the oral tabs condition vs. only one in the mini-dose glucagon condition and none in the control or basal rate reduction conditions. These results show promising early efficacy for Xeris’ G-Pen Mini as a solution for exercise-induced hypoglycemia in type 1 diabetes – compared to control, basal insulin reduction, and oral glucose tabs, this mini-dose of glucagon minimized both hypoglycemia and hyperglycemia during and immediately after exercise. This study is particularly important since it also  shows how much more effective a small dose of glucagon is if given just before exercise, rather than waiting until hypoglycemia develops during exercise, the latter of which is repeatedly observed in duel hormone studies using glucagon in artificial pancreas  studies. The poster concludes that this phase 2 data supports a larger, longer-term study of Xeris’ G-Pen Mini, which we’d love to see. Xeris currently has one of the most advanced clinical programs for glucagon, and we’ll be watching eagerly for updates. See our glucagon competitive landscape for more information.

Ultra-Rapid Biochaperone Lispro Improves Post-Prandial Glucose Excursions Versus Insulin Lispro in a 14-day Treatment Study in Subjects with Type 1 Diabetes (964-P)

G Andersen, G Meiffren, D Lamers, A Ranson, B Alluis, M Gaudier, O Soula, T Heise, and S Bruce

Adocia’s ultra-rapid BioChaperone Lispro (BCLIS) demonstrated an accelerated absorption profile and significant reductions in postprandial glucose excursions compared with insulin lispro (Lilly’s Humalog) in people with type 1 diabetes. The randomized, monocentric, double-blind, comparator-controlled 14-day phase 1 crossover trial enrolled 36 participants (mean age 45 ± 12 years) with type 1 diabetes. Patients were randomized to receive bolus doses of either BCLIS or insulin lispro for 14 days. While in the inpatient setting for days 1-3 and 14 of the study, patients received the insulin they had been assigned to 15 minutes before, immediately before, or 15 minutes after an individualized mixed-meal, with blood samples and lispro concentrations subsequently measured. Patients continued the insulin regimens to which they had been randomized in the outpatient setting on days 4-13, and additionally self-measured plasma glucose (SMPG) levels four times daily.  BCLIS insulin had a “faster-in/faster-out” profile than insulin lispro. BCLIS dosing additionally resulted in significantly lower post-meal glycemic excursions as compared to insulin lispro  if the insulin was dosed immediately before the meal’s start or 15 minutes thereafter. Notably, postprandial glycemic excursion profiles were similar between BCLIS injected fifteen minutes after a meal’s start and insulin lispro injected immediately before a meal’s start. Mean outpatient SMPG values didn’t differ significantly BCLIS and insulin lispro. Safety profiles were also similar between the treatment groups. 

Ultra-Rapid Biochaperone Lispro Improves Postprandial Blood Glucose Control versus Humalog in a 14-day Treatment Study in Subjects with Type 2 Diabetes (994-P)

T Heise, G Meiffren, D Lamers, B Kronshage, A Ranson, B Alluis, M Gaudier, E Anastassiadis, O Soula, and S Bruce

Adocia’s ultra-rapid BioChaperone lispro (BCLIS) demonstrated an accelerated absorption profile and significant reductions in postprandial glucose control versus insulin lispro (Lilly’s Humalog) in people with type 2 diabetes. The randomized, monocentric, double-blind, comparator controlled 14-day crossover phase 1 trial enrolled 51 participants (mean age 62 ± 9 years) with type 2 diabetes. Participants were randomized to receive either individualized BCLIS or insulin lispro bolus doses with meals. On inpatient days 1-2 and 13-14, patients received the insulin to which they had been randomized with an individualized mixed-meal, after which blood samples and lispro concentrations were assessed. In the outpatient setting on days 3-12, patients continued their assigned insulin regimens and measured their plasma glucose (SMPG) levels.  BCLIS insulin had a “faster-in/faster-out” profile than insulin lispro. BCLIS additionally resulted in significant reductions in post-prandial glucose exposure for up to three hours after dosing as compared with insulin lispro.  Differences in glycemic excursions between treatments were most pronounced on days 13-14. Mean outpatient SMPG values didn’t differ significantly between BCLIS and insulin lispro, but notably, similar values were achieved with 10% lower BCLIS doses. Treatment with BCLIS was safe and well tolerated. 

SORELLA-1: Similar One-Year Efficacy and Safety in People with T1DM Using SAR342434 or Insulin Lispro in Combination with Insulin Glargine (Gla-100) (1003-P)

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

This poster featured one year data from the phase 3 SORELLA 1 study, demonstrating the non-inferiority of Sanofi’s SAR34233, a rapid-acting follow-on biologic to insulin lispro, to the originator product (Lilly’s Humalog) in people with type 1 diabetes, reinforcing the 26-week findings presented at ADA 2016. Developed as a rapid acting follow-on product to Humalog, SAR has an identical amino acid sequence to that of insulin lispro and a previous clamp study determined that SAR was similar in pharmacokinetic exposure and pharmacodynamics activity to insulin lispro. In the study, 507 people with type 1 diabetes were randomized to receive either a multiple daily injection regimen of SAR or insulin lispro in addition to once-daily insulin glargine. At 52 weeks, the SAR and insulin lispro groups exhibited a LS mean difference in A1c of 0.06% (95% CI: -0.084% to 0.197%), solidly indicating non-inferiority between the two drugs. In addition, both groups showed similar post-prandial glucose excursions and insulin dosages. Almost all patients reported at least one episode of hypoglycemia, but with similar incidence between the SAR and insulin lispro groups for all categories of hypoglycemia: severe (13.5% vs. 13.4%), documented symptomatic <70 mg/dl (87.3% vs. 89.8%), and asymptomatic <70 mg/dl (97.2% vs. 97.6%).Furthermore, in both SAR- and insulin lispro- treated patients, anti-insulin lispro antibody incidence levels were similar (62.5% vs. 63.1% respectively). Each treatment group had two patients who discontinued treatment due to a treatment-emergent adverse event: 54.4% of SAR-treated and 55.5% of insulin lispro-treated participants reported any adverse event. Thus, the study’s findings concluded that SAR was just as effective and well-tolerated as insulin lispro in people with type 1 diabetes.

Similar Glucose Control, Postprandial Glucose Excursions, and Safety in People with T2DM Using SAR342434 or Insulin Lispro in Combination with Insulin Glargine (Gla-100): SORELLA 2 Study (1004-P)

KM Derwahl, T Bailey, K Wernicke-Panten, L Ping, and S Pierre

This poster featured initial phase 3 data from the SORELLA 2 study, demonstrating the non-inferiority of Sanofi’s SAR34233, a rapid-acting follow-on biologic to insulin lispro, to the originator product (Lilly’s Humalog) in people with type 2 diabetes. Developed as a rapid acting follow-on product to Humalog, SAR has an identical amino acid sequence to that of insulin lispro and a previous clamp study determined that SAR was similar in pharmacokinetic exposure and pharmacodynamics activity to insulin lispro. In the study, 505 people with type 2 diabetes (mean age 62 years; mean BMI 32 kg/m3; mean A1c 8%) were randomized to receive either a multiple daily injection regimen of SAR or insulin lispro in addition to once-daily insulin glargine. At 26 weeks, the SAR and insulin lispro groups exhibited a LS mean difference in A1c of -0.07% (95% CI: -0.215% to 0.067%), solidly indicating non-inferiority between the two drugs. In addition, both groups showed similar post-prandial glucose excursions and insulin dosages. Almost all patients reported at least one episode of hypoglycemia, but with similar incidence between the SAR and insulin lispro groups for all prespecified categories of hypoglycemia: severe (2.4% vs. 1.6%), documented symptomatic <70 mg/dl (60.1% vs. 66.3%), and asymptomatic <70 mg/dl (35.2% vs. 37.3%).Furthermore, in both SAR- and insulin lispro- treated patients, anti-insulin lispro antibody incidence levels were similar (38.4% vs. 36.7% respectively). Each treatment group had two patients who discontinued treatment due to a treatment-emergent adverse event: 46.6% of SAR-treated and 42.9% of insulin lispro-treated participants reported any adverse event. There was one death in the SAR arm and two deaths in the insulin lispro arm, but these were unrelated to the study drug. Thus, the study’s findings concluded that SAR was just as effective and well-tolerated as insulin lispro in people with type 2 diabetes.

Efficacy and Safety of Mini-Dose Glucagon for Treatment of Nonsevere Hypoglycemia in Adults with Type 1 Diabetes (1068-P)

MW Haymond, S Dubose, MR Rickels, H Wolpert, VN Shah, JL Sherr, RS Weinstock, S Agarwal, AS Verdejo, MJ Cummins, B Newswanger, and RW Beck

Xeris’ G-Pen Mini was investigated in 17 adults with type 1 diabetes as a treatment for nonsevere hypoglycemia. In a randomized crossover design, participants spent three weeks with mini-dose glucagon and three weeks with oral glucose tabs to treat any cases of mild hypoglycemia. The primary endpoint of “success” was defined as blood glucose ≥50 mg/dl 15 minutes following treatment and blood glucose ≥70 mg/dl 30 minutes following treatment – 94% of patients in the mini-dose glucagon arm achieved success vs. 95% of patients in the glucose tabs arm. BGM and CGM data showed a similar profile for the G-Pen Mini vs. oral glucose tabs. In the first hour post-hypoglycemic event, people in the glucagon group spent 62% of time-in-range vs. 67% for people in the glucose tabs group (p=0.86). In the first two hours post-hypoglycemic event, participants in both groups spent a mean 79% of time-in-range (p=0.49). Time <70 mg/dl was a mean 35% for the glucagon group one hour post-hypoglycemia vs. 33% for the glucose tabs group (p=0.95). Two hours post-hypoglycemia, these values were 20% and 19%, respectively (p=0.63). The non-significant p-values indicate the G-Pen Mini’s non-inferiority vs. oral glucose tabs as a treatment for mild hypoglycemia, but the poster points out other distinct advantages to mini-dose glucagon: Namely, carbohydrates as a solution to nonsevere hypoglycemia lead to excess caloric intake and excess hyperglycemia, all of which could be avoided with Xeris’ G-Pen Mini. After six weeks of the study, participants were asked to choose between the two treatment options for an additional three weeks – ~50% opted to continue mini-dose glucagon. Injection discomfort and nausea were the primary reported adverse events associated with the G-Pen Mini, affecting 15 and three participants, respectively. Overall, these results support continued investigation of Xeris’ product for mild-to-moderate hypoglycemia, and we look forward to future data readouts. Xeris is an industry leader right now in the glucagon competitive landscape, and we’re very happy to see forward progress on the company’s various glucagon candidates.

A Phase 1b, Randomized, Placebo-Controlled, Multiple-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AMG 876, a Novel Fc-FGF-21 Fusion Protein, in Subjects with Type 2 Diabetes Mellitus (1069-P)

L Abuqayyas, M Tracy, S Smith, A Anderson, and A Kaufman

A phase 1b study of Amgen’s FGF21 candidate AMG 876 found the agent to be safe and well-tolerated at various doses (7 mg, 21 mg, 70 mg, or 140 mg either once- or twice-weekly). In total, there were 43 treatment-emergent adverse events among 52 patients with type 2 diabetes randomized to AMG 876 (83%) vs. 12 such events among 17 patients randomized to placebo (71%). There were no serious adverse events or fatalities throughout the trial, although only one participant in the placebo arm discontinued treatment vs. five participants in the FGF21 arm – four of these were in the highest-dose group, reporting (i) vomiting, (ii) diarrhea, (iii) tremors/nausea, and (iv) tremors. Efficacy was investigated as a secondary endpoint in this phase 1b trial. The poster reports significant reductions in fasting and postprandial glucose with AMG 876 vs. placebo. Amgen’s candidate was also associated with a clinically-meaningful decrease in triglyceride levels and an increase in HDL cholesterol vs. placebo. FGF21 analogs seem to be getting more attention in the diabetes/obesity fields of-late, with new pipeline candidates from Amgen (for type 2 diabetes), Novo Nordisk (for obesity), BMS (for NASH), and Roche (indication not yet announced). There’s a lot of interest brewing in this potential new therapy class, but we also recognize that all of these candidates remain extremely early-stage and will have a long road ahead through clinical development before possibly reaching the commercial market. Notably, both Lilly and Pfizer discontinued their FGF21 candidates for type 2 diabetes following lackluster glucose-lowering results from phase 2 trials.

Results of a Phase 2 Study of the Oxyntomodulin (OXM) Analogue LY2944876 in Patients with Type 2 Diabetes (T2DM) (1070-P)

M Sheetz, R Bray, LS Tham, C Jones, J Kinsella, and R Violante-Ortiz

Lilly presented full phase 2 results for its PEGylated GLP-1/glucagon dual agonist, oxyntomodulin analog LY2944876 in patients with type 2 diabetes. In this 24-week trial, 420 patients were randomized to once-weekly injections of one of four doses of LY2944876 (10 mg, 15 mg, 30 mg, or 50 mg), exenatide once-weekly (AZ’s GLP-1 agonist Bydureon), or placebo. At both week 12 and week 24, LY2944876 demonstrated superiority to placebo and non-inferiority to exenatide for the primary endpoint of A1c reduction. A1c reductions were largely dose-dependent for LY2944876 and ranged from ~0.8% to ~1.4%. At the highest 50 mg dose, LY2944876 produced statistically superior weight reductions compared to exenatide and placebo (p=0.044 and p=0.007, respectively). However, the finding did not achieve the predefined criterion for superior weight loss (a posterior probability [PP] of ≥60% by Bayesian analysis with a margin of 1.5 kg – LY2944876 only achieved a PP of 29.4%). Lilly also shared several additional results of interest. At week 24, significantly more patients in the 50 mg dose group had achieved a weight loss of ≥5% body weight (35.5%) than in the placebo (11.8%, p=0.004) or exenatide (18.3%, p=0.025) groups. That said, at week 24, the proportion of participants achieving A1c ≤7% or ≤6.5% in the 50 mg dose group was comparable to that of the exenatide arm. Lilly also reported that fasting glucagon levels were reduced by approximately 40% in the 50 mg group, compared to a ~12% reduction in the exenatide group. There was no significant chance in blood pressure between any of the groups. Heart rate increased in the two highest dose groups for the dual agonist, but the increase was less than the increase observed with exenatide (p<0.05). Adverse events associated with the dual agonist were similar to what might be expected with a selective GLP-1 agonist, largely consisting of GI events.

  • Lilly previously partnered with Transition Therapeutics on the development of this candidate, before declining to advance the candidate into phase 3, despite its status as a potential first-to-market GLP-1/glucagon dual agonist. Transition Therapeutics – and this candidate – have since been acquired by OPKO Health, which is investigating a potential obesity indication for this drug, rather than a type 2 diabetes indication. We previously learned that the topline results met the trial’s primary endpoint and demonstrated non-inferiority to exenatide in terms of A1c and superiority in terms of body weight. Full results in hand, however, it’s clear that the weight loss superiority did not meet the predefined criteria that Lilly was looking for. Given its robust portfolio of newly-launched diabetes drugs and early-stage pipeline efforts, Lilly understandably has a very high internal threshold for continued clinical development of its candidates – and particularly for advance into phase 3. Lilly also appears to somewhat favor its internally-developed diabetes candidates to licensed molecules (with the notable exception of the very successful BI alliance, and its acquisition of Locemia’s nasal glucagon). Indeed, Lilly’s phase 1 pipeline includes an internally-developed, once-weekly GLP-1/glucagon dual agonist for type 2 diabetes and NASH, a candidate that was added after the decision not to pursue the Transition Therapeutics partnership further. See our GLP-1/glucagon dual agonist competitive landscape an overview of the robust industry investment in this area.

The Effect of NNC0090-2746, a Dual GIP/GLP-1 Receptor Agonist (RA), on Glycemic Control, Plasma Cholesterol, and Body Weight in Subjects with Type 2 Diabetes: A Phase 2a Randomized Clinical Trial (1071-P)

JP Frias, EJ Bastyr, L Vignati, M Tschöp, C Schmitt, K Owen, RH Christensen, and R DiMarchi

This poster featured phase 2a data deonstrating significant improvements in glycemic control, body weight, and cholesterol with Novo Nordisk’s GIP/GLP-1 receptor agonist NNC0090-2746 compared to placebo after 12 weeks in people with type 2 diabetes. These promising results come on the heels of a separate poster presented at ADA overviewing phase 1 evidence that the candidate is well-tolerated in doses of up to 2 mg in people with type 2 diabetes and can produce meaningful reductings in fasting, post-prandial, and 24 hour profile plasma glucose, as well as A1c reductions of up to 0.67%, after two weeks (1095-P). In this phase 2a study, 108 people with type 2 diabetes (average age 55 years, average A1c 8.3%, average diabetes duration 8 years) were randomized to receive NNC009-2746, placebo, or Novo Nordisk’s GLP-1 agonist Victoza (liraglutide). The Victoza arm was open-label, and this analysis only statistically compares the double-blind NNC009-2746 and placebo arms. After 12 weeks, participants taking the GIP/GLP-1 agonist showed significant improvement in the primary endpoints of A1c reduction: relative to placebo, A1c was reduced 0.63% in the treatment group (95% CI: -0.93 to -0.33; p<0.0001). The GIP/GLP-1 agonist also produced significant reductions in mean 7-point SMPG (-31.7 mg/dl, p<0.0001) and FPG (-38.2 mg/dl, p<0.0001). As for the key secondary endpoint of body weight, NNC009-2746 produced significant weight loss relative to placebo at 8 weeks (-1.8% treatment difference, p=0.0141) but the trend lost significance at week 12 (-1.6%, p<0.05). However, significant improvements were maintained throughout the entire study in various adipose biomarkers and lipid parameters, including total cholesterol (treatment difference -0.92  mg/dl, p=0.02) and plasma leptin levels (treatment difference -0.78 mg/dl, p=0.018). Interestingly, a post-hoc analysis revealed a significant interaction between baseline A1c and body weight reduction such that participants with a baseline A1c  below 8.5% lost significantly more weight with the GIP/GLP-1 agonist relative to placebo than those with an A1c above 8.5% (p for interaction = 0.041), suggesting that the maximum benefit of NNC0090-2746 with respect to weight loss is obtained by people with already near-target glycemic control. As for adverse events, the treatment group experienced more adverse events than the placebo group (65% vs. 42%), driven by a higher proportion of gastrointestinal adverse events (35% vs. 17%) as expected with agents in the GLP-1 agonist family. Together, these results support the safety and efficacy of NNC0090-2746 for impoving glycemic control and reducing body weight (especially for those already with good glycemic control).

Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Ascending Doses of the Novel Dual GIP/GLP-1 Agonist RG7697 in Patients with Type 2 Diabetes Mellitus (1095-P)

C Schmitt, A Portron, S Jadidi, N Sarkar, and R Dimarchi

This poster shared phase 1 data on Roche’s now-discontinued GLP-1/GIP dual agonist, RG7697.  In the multiple ascending dose study, patients with type 2 diabetes (n=56) on a stable dose of metformin for at least two months were randomized to receive either once-daily subcutaneous injections of RG7697 (doses ranging from 0.25-2.5 mg) or placebo for two weeks. Daily injections of RG7697 were generally well-tolerated, although the most frequent adverse events included hypoglycemia, diarrhea, nausea, headache, and decreased appetite. One patient withdrew from the study due to adverse events of hypokalemia, dehydration, and acute renal failure. Reversible treatment-related increases in heart rate, lipase, and amylase were recorded. PK steady state was achieved after seven days, and PD data showed a dose-dependent glucose-lowering effect vs. placebo, with mean absolute A1c reductions between 0.41% and 0.67% after 16 days. Postprandial glucose concentrations were reduced 37% from baseline and postprandial insulin concentrations were reduced at doses of the agent ≥1.1 mg, suggesting an increase in insulin sensitivity. That said, efficacy was a secondary endpoint in this trial, and ultimately a combination of these safety and efficacy findings led to Roche’s decision to discontinue RG7697 from its pipeline. GLP-1/GIP dual agonists present an exciting advancement in diabetes therapy, although the most advanced candidates on this competitive landscape remain very early-stage, in phase 1. We hope that these results, even though the candidate was discontinued, help inform other existing clinical development programs for GLP-1/GIP dual agonists.

Potent Body Weight Loss and Efficacy in a NASH Animal Model by a Novel Long-Acting GLP-1/Glucagon/GIP Tri-agonist (HM15211) (1139-P)

IY Choi, JS Lee, JK Kim, YJ Park, S Jung, YH Kim, and SC Kwon

This poster demonstrates preliminary evidence for the safety and efficacy of Hamni’s novel long-acting GLP-1/glucagon/GIP triple agonist HM15211 in rodent models of obesity and NASH. In rodents with diet-induced obesity, the triple agonist produced 35% body weight loss over four weeks, versus 19% weight loss with the GLP-1 agonist liraglutide (Novo Nordisk’s Victoza; p<0.001). The mechanism underlying this may be energy expenditure; despite similar food intake, animals treated with the triple agonist showed an energy expenditure of nearly 14 kcal/hour, versus only 13 kcal/hour for liraglutide and 12 kcal/hour with placebo (p<0.001). The efficacy of the GLP-1/glucagon/GIP triple agonist extends beyond obesity to NASH, demonstrating significant improvements over both liraglutide and placebo in measures of NASH prognosis, including hepatic triglycerides, hepatic thiobarbituric acid, lobular inflammation, and overall NAFLD Activity Score (NAS). Based on these promising results,  we expect the candidate to advance to in-human studies and we very much look forward to the phase 1 data.

Low Weekly Doses of IONIS-GCGRRX, a Second-Generation Antisense Glucagon Receptor Antagonist, Caused Significant Improvements in Glycemic Control in T2DM Patients on Stable Metformin Therapy (1158-P)

E Morgan, L Tai, SB Jung, R Geary, and S Bhanot

Ionis presented results from its phase 2b dose optimization study of glucagon receptor antagonist IONIS-GCGRRx on a poster (topline data was released in early January 2017). The 75 mg dose of the agent (n=21 type 2 diabetes patients on stable metformin therapy at baseline) was associated with a 1.6% A1c decline vs. a 0.2% mean A1c drop for participants (n=23) randomized to placebo (p<0.001). The 50 mg dose (n=20) was associated with a mean 0.9% A1c reduction (p<0.05 vs. placebo). Moreover, 67% of people in the 75 mg arm achieved A1c-lowering ≥1% vs. 9% of people in the placebo arm (p<0.001) and 45% of people in the 50 mg arm (p<0.01 vs. placebo). And, 38% of the 75 mg group achieved target A1c <7% (from a baseline 8.8%) vs. 9% of the placebo group (p<0.05). GLP-1 levels were increased in a dose-dependent fashion with IONIS-GCGRRx, while participants on placebo experienced a mean decline in GLP-1. While all of this efficacy data points to the superiority of the 75 mg dose, the poster also reports a 1.2x increase in ALT liver enzymes in this treatment arm vs. a mean decrease in the 50 mg arm. There were three confirmed cases of ALT levels increasing more than 3x in the 75 mg group, and none in the 50 mg group. The poster concludes that IONIS-GCGRRx could be titrated on an individual basis between 50-75 mg, since there was no statistically significant correlation between A1c-lowering and rise in ALT liver enzymes. On the whole, these results support continued clinical development for Ionis’ glucagon receptor antagonist candidate, possibly in combination with different oral type 2 diabetes therapies (such as SGLT-2 inhibitors).

  • IONIS-GCGRRx is a potential first-in-class glucagon receptor antagonist, ahead of Ligand’s phase 2 candidate. While we’re excited to note clinical progress, we’re also aware of safety issues related to glucagon receptor antagonists, which led to the discontinuation of Lilly’s and Pfizer’s in-class candidates in 2Q15 and 4Q16, respectively. Pfizer recently added a glucagon receptor blocker to its phase 1 pipeline, which hints at the company’s continued confidence in this therapeutic target despite underwhelming results from its earlier phase 2 candidate.

Symposium: ADA Pathway to Stop Diabetes

Daniel Ceradini, MD (NYU Langone Medical Center, New York, NY); Joshua Thaler, MD (University of Washington, Seattle, WA); Praveen Sethupathy, MD (Cornell University, Ithaca, NY); Kathleen Page, MD (USC, Los Angeles, CA); Phillip White, MD (Duke University, Durham, NC)

As always, the ADA Pathway to Stop Diabetes symposium offered an inspiring glimpse at the future of diabetes management. We were particularly excited to hear from Dr. Zhen Gu (University of North Carolina, Chapel Hill, NC) on the variety of smart insulin delivery approaches his lab is researching. Echoing his talk at the JDRF Mission Summit in January, Dr. Gu discussed the merits of hypoxia-sensitive vs. pH-sensitive delivery systems and his early forays into the possibility of using red blood cells for smart insulin delivery. In his view, the main challenges facing the smart insulin field today are (i) achieving a fast response comparable to normal beta cell activity; (ii) avoiding hypoglycemia; (iii) achieving ease of administration; and (iv) ensuring biocompatibility. Other highlights from the symposium included:

  • Dr. Daniel Ceradini (NYU Langone Medical Center, New York, NY) presented data showing that that siRNA-mediated Keap1 knockdown resulted in significantly accelerated diabetic wound closure in a humanized mouse model. The approach reduced wound burden by 60% and could potentially allow for improvements in quality of life and significant reductions in healthcare costs. We were very excited to see this research given this is an enormously expensive complication and one that is addressable.
  • Dr. Joshua Thaler (University of Washington, Seattle, WA) discussed his research on how astrocyte and microglial inflammatory signaling promotes obesity susceptibility in high fat diet-fed mice.
  • Dr. Praveen Sethupathy (Cornell University, Ithaca, NY) discussed recent findings demonstrating that a high-fat diet alters small intestinal morphology and physiology. His lab found that 20 weeks on this diet led to a significant increase in epithelial proliferation and a disproportionate allocation of stem cells and progenitors. In a promising proof of concept in fruit flies, he found that overexpression of a particular mRNA in stem cell compartments can almost completely suppress this proliferative response.
  • Dr. Kathleen Page (USC, Los Angeles, CA) summarized recent findings implicating central adiposity in childhood as an early indicator of intrauterine exposure to gestational diabetes and maternal adiposity. We find the subject of epigenetics extremely interesting and hope to see more on this as an approach to reducing obesity longer-term.
  • Dr. Phillip White (Duke Molecular Physiology Institute, Durham, NC) presented findings demonstrating that inhibition of the enzyme BDK improves glucose tolerance and lowers hepatic triglyceride content. BDK is an enzyme that regulates branched-chain amino acid metabolism along with PPM1K; its beneficial effects appear to be exerted through regulation of ATP-citrate lyase.

Responsive Vesicles Integrated with Transcutaneous Patches for Glucose-Mediated Insulin Delivery

Zhen Gu, PhD (University of North Carolina, Chapel Hill, NC)

Echoing his talk at the JDRF Mission Summit in January, Dr. Zhen Gu discussed several approaches to glucose-responsive insulin delivery that his iMedication lab is researching. Two projects – the microgel and nano-network approaches – use the enzyme glucose oxidase to convert glucose to gluconic acid and create an acidic environment that activates the release of insulin. While these approaches have shown some positive effects in preclinical models, Dr. Gu explained that response speed has been a challenge, as the body’s buffering ability makes it difficult to immediately generate an acidic environment. Therefore, the lab is also exploring a hypoxia-sensitive insulin patch that releases insulin when oxygen levels fall (both glucose and oxygen are consumed in the glucose oxidase reaction). Finally, Dr. Gu mentioned his lab’s preliminary efforts to use red blood cells for smart insulin delivery: the cells are coated with modified insulin that detaches in response to high glucose. In addition to speed, other key challenges that Dr. Gu cited include the risk of hypoglycemia, ease of administration, and biocompatibility.

Symposium: ADA Diabetes Symposium – Emerging Therapeutic Targets and Mechanisms of Action

Single-Molecule Combinatorial Therapeutics for Obesity and Diabetes

Matthias Tschöp, MD (Helmholtz Diabetes Center, Munich, Germany)

Dr. Matthias Tschöp offered an intriguing vision of a future in which patients with metabolic dysfunction could receive personalized treatment with dual or triple agonists that target their specific metabolic defects. He explained that a truly effective treatment for obesity probably needs to target the brain and that modulating endogenous gut-brain communication pathways is likely safer than directly altering neurotransmission. He reviewed published data showing beneficial effects of GLP-1/glucagon dual agonists and a GIP/GLP-1/glucagon triagonist on several metabolic parameters. He acknowledged that it is counterintuitive to use a glucagon agonist to reduce blood glucose and body weight but stressed that his lab has done a significant amount of mechanistic research to demonstrate that glucagon receptor agonism does have those effects in this case. The group’s current working hypothesis for that aspect of the triagonist’s mechanism is that the molecule leads to increased energy expenditure in adipose tissue by acting through FGF21 and adiponectin. Dr. Tschöp also reviewed data (presented as poster 1071-P) demonstrating significant and sustained improvements in glycemic control and body weight with GLP-1/GIP dual agonist NNC0090 in patients with type 2 diabetes. The study also found some reduction in total cholesterol and leptin, and the overall results suggest that the maximal weight benefit of this therapy occurs in patients with lower baseline A1c. Dr. Tschöp closed by briefly mentioning several other multi-agonist compounds his lab is working on, including GLP-1/estrogen, GLP-1/dexamethasone, glucagon/T3, and GLP-1/PPAR alpha dual agonists.

Questions and Answers

Q: It seems like you’ve hit a bunch of home runs by putting two or three things together. What doesn’t work?

A: This is always a bit misleading. Of course we’ve tried hundreds of things that don’t work. Most of my hypotheses were wrong and there’s lots of trial and error.

Q: At the end you mentioned interactions between estrogen and some other agents. Is there any data in rodent, primate, or human studies to suggest differential responses by sex?

A: We have been asked to perform those studies for the revision of our paper. GLP-1/estrogen works comparably in male and female rodents. The protection of the islet, which is quite striking, will probably be more prominent in rodents than humans.

Q: Does the target cell need to have all three receptors for the triagonist to work?

A: The simple answer is no. It is sufficient that the target cell has one receptor. The molecule can only bind one receptor at a time. We’ve dialed the affinity into the molecule so that if you give 100 molecules, 30 will bind to one receptor, 40 to another, etc. There’s no simultaneous binding to the best of our knowledge.

Q: If the agonist can bind to separate the receptors, as it comes off one could it get picked up by another on the same cell? Could there be a kinetic effect of the cell having multiple receptors?

A: I’m not sure but there’s no data indicating that.

Q: You talked about targeting the brain but your data didn’t relate to that. Have you done any ICV injection studies?

A: I didn’t include some of that data at the end for the sake of time. We haven’t done ICV injections but that’s currently going on. It’ll be more important to find out how much of our compounds is crossing the blood-brain barrier. My hunch is it’s not that much but that they are acting on the brain. When you knock out the brain GLP-1 receptor, you see a reduction in benefit. Perhaps the compounds are getting into an area of the brain with fenestrated capillaries like the arcuate nucleus.

Q: Could these compounds really be competitive antagonists that are decreasing the activity of native agonists?

A: We discussed this possibility early on. We’re certain now that it’s glucagon receptor agonism based on a number of studies. It’s really agonism, not relative antagonism.

Symposium: Technical Innovations in Islet Transplantation—Novel Approaches

Engineering Novel Encapsulation Platforms for Islets

Cherie Stabler, PhD (University of Florida, Gainesville, FL)

Dr. Cherie Stabler highlighted several novel beta cell encapsulation approaches that she views as particularly promising, including microencapsulation, nanoscale coatings, and new coatings created by covalent layer-by-layer encapsulation. She emphasized how these efforts can address several key considerations in the effort to fabricate nano-scale barriers to encapsulate pancreatic islets, such as ensuring a controllable thickness (through nanoscale control of capsule) and long-term mechanical stability (through covalently linking layers). According to Dr. Stabler, a “home run”  in encapsulation would involve resolving the immunological problem, the cell source problem, and the transplant problem. Islet encapsulation must solve issues of permeability, biocompatibility, and stability as well. The material must be permeable enough to allow nutrients such as glucose and oxygen to come into the islet and for insulin to leave the islet, while also being non-permeable to antibodies. Many materials degrade when put into the body, so the material must be stable enough to survive. In conventional microencapsulation, islets suffer from poor delivery of oxygen and nutrients, sluggish glucose response and insulin secretion, exacerbated by transplant site. ViaCyte has experienced some of these challenges firsthand in its phase 1/2 trial of PEC-Encap – due to the challenges with fibrosis and variable patient responses, the company has de-prioritized this effort to some extent and is instead focused on PEC-Direct, a direct vascularization product that does not protect ViaCyte’s stem cell-derived islet progenitor cells from the immune system (requiring patients to take immunosuppressants. We’re so very glad that very smart people like Dr. Stabler are hard at work at creating next-generation encapsulation devices that can hopefully avoid some of the pitfalls of the first-generation efforts.

Special Lectures and Addresses: National Scientific & Health Care Achievement Awards Presentation and Outstanding Scientific Achievement Award Lecture

Outstanding Scientific Achievement Award Lecture—Energy Sensing and Metabolism—Implications for Treating Diabetes

Gregory Steinberg, PhD (McMaster University, Hamilton, Ontario, Canada)

In a fascinating summary of his award-winning basic science research, Dr. Gregory Steinberg shared how his work on energy sensing and metabolic regulation could create exciting, novel therapies for diabetes treatment. Steinberg centered his talk around AMPK, a ubiquitous protein that is activated by metformin and exercise, and explained that this protein kinase is like a fuel gauge that tells the cell when to fill up with energy. He continued by explaining that increased AMPK levels may increase insulin sensitivity and glucose tolerance and reduce liver lipids. Simultaneously metformin also increases levels of GDF15, a protein that suppresses appetite.’ Steinberg explained that his most recent work has been in finding pharmacological agents that could activate these fuel gauges. He further suggested that AMPK is required for norepinephrine induced transformation of white adipose tissue into brown adipose tissue (BAT), based on evidence in mice lacking AMPK demonstrating that they are not able to regulate their own body temperature and develop insulin resistance despite eating the same diet as wild type mice. While there is no established method for restoring BAT activity in obesity and diabetes, Steinberg explained that that peripheral serotonin becomes elevated with high fat western diets and acts as brake to inhibit norepinephrine-induced activation of BAT. He noted that reduction of peripheral serotonin increases BAT activity and protects against obesity and insulin resistance in mice. Dr. Steinberg concluded his talk by circling back to his research’s relevancy to patients with type 2 diabetes, arguing that further examination of how to manipulate these cellular fuel gauges could lead to important, groundbreaking therapies in the treatment of type 2 diabetes.

 

-- by Abigail Dove, John Erdman, Helen Gao, Stephanie Kahn, Payal Marathe, Emily Regier, Lisa Rotenstein, Maeve Serino, Emily Yang, and Kelly Close