Diabetes Canada 2017
Abstract
Ann M. Carracher, Payal H. Marathe, and Kelly L. Close are of Close Concerns (http://www.closeconcerns.com), a healthcare information company focused exclusively on diabetes and obesity care. Close Concerns publishes Closer Look, a periodical that brings together news and insights in these areas. Each month, the Journal of Diabetes includes this News feature, in which Carracher, Marathe, and Close review the latest developments relevant to researchers and clinicians.
The 20th annual Diabetes Canada Professional Conference took place in November 2017 in Edmonton, Alberta, Canada, featuring Dr Daniel Drucker on 30 years of incretin biology research and Dr David Matthews on implications of the Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes (CANVAS) trial,1 among other sessions. Dr Drucker reviewed the history of glucagon-like peptide-1 (GLP-1) receptor agonists, from the discovery of the incretin effect, to the isolation of the exendin peptide from Gila monster venom, to the commercialization of GLP-1 receptor agonists, starting with approval of twice-daily exenatide, then branded as Byetta by Amylin Pharmaceuticals (San Diego, CA, USA), and now marketed by AstraZeneca (Cambridge, UK). Dr Drucker continued his history up through the demonstration of a cardioprotective benefit for Novo Nordisk's (Copenhagen, Denmark) Victoza (liraglutide)2 and semaglutide.3 According to Dr Drucker, the next era of the GLP-1 agonist story will hinge on elucidating the mechanism underlying this cardioprotective effect. Dr Drucker points out, “If you want to make drugs better, with a next-generation version with even more potent glucose-lowering and even more cardioprotection, then you do need to know how they work to know where to focus attention for innovation.” Dr Drucker's and his laboratory's leading hypothesis on cardioprotection is inflammation. The majority of GLP-1 receptors in the immune system are located in intestinal intraepithelial lymphocytes, far from where glucose regulation takes place. Glucagon-like peptide-1 receptors have this entirely distinct, glucose-unrelated role in the lower gut, where they are responsible for coordinating the anti-inflammatory response.
Dr David Matthews, lead CANVAS investigator, discussed the complexities of modern clinical trial design and interpretation. The CANVAS trial found a 14% risk reduction for three-point major adverse cardiac events (MACE; non-fatal myocardial infarction [MI], non-fatal stroke, or cardiovascular death) with Johnson & Johnson's (New Brunswick, NJ, USA) canagliflozin (Invokana) versus placebo, but also found a nearly twofold risk for lower extremity amputations with canagliflozin,1 which was not seen for Eli Lilly (Indianapolis, IN, USA) and Boehringer Ingelheim's (Ingelheim, Germany) empagliflozin (Jardiance) in the Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME) study.4 Dr Matthews underscored that these trials involved different baseline study populations, different trial durations, and a different process for event adjudication. On one hand, this heterogeneity lends greater credence to the notion of a cardioprotective class effect for sodium–glucose cotransporter 2 (SGLT-2) inhibitors, because significant risk reduction for MACE was duplicated in these two distinct trials. However, as for whether the amputation signal could be a class effect, the distinctions in trial design make this an unanswerable question.
Diabetes Technology Meeting 2017
The 17th annual Diabetes Technology Meeting took place in November in Bethesda, Maryland, USA. Dr Lutz Heinemann called into question the quality of insulin, presenting preliminary results from a basic mass spectrometry study in which colleague Dr Alan Carter found that only one of 18U100 regular and neutral protamine Hagedorn (NPH) samples procured at different pharmacies approached a concentration of 100 units/mL. All nine regular insulin samples hovered between 13.9 and 28.7 units/mL, suggesting someone could be injecting one-eighth as much insulin as he/she thought. The NPH samples were even more variable in this analysis, ranging from 35.1 to 94.2 units/mL. Dr Heinemann shared his intuition that the cold supply chain may not working as expected and Dr David Rodbard suggested that perhaps the vials experience degradation during transit. Dr Heinemann called for a deeper analysis into the issue, which affects real-world patient experience and success taking insulin therapy. He also acknowledged that there could be measurement error in this preliminary research.
| Company updates | |
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| August 1, 2017 | ViaCyte (San Diego, CA, USA) announced that the first clinical trial of PEC-Direct is officially underway, investigating the islet cell replacement therapy for high-risk type 1 diabetes (T1D). The first patients were implanted with the product candidate by the beginning of August, slightly delayed from the projected timeline (first half of 2017) for clinical trials to commence. The first participants were treated at the University of Alberta and UC San Diego, and the University of Minnesota is now actively enrolling patients as well. In this first cohort, individuals received multiple smaller cell-filled devices that will be removed at specific time points to evaluate implant engraftment, the key question being, are these cells healthy and showing signs of maturation into pancreatic islet cells, including insulin-secreting β-cells? A second cohort of up to 40 patients will start enrollment later this year to evaluate efficacy. The company expects enrollment to be fully complete in the second half of 2018, with efficacy results approximately 6 months later. ClinicalTrials.gov lists an expected completion date of December 2020 for the Phase 1/2 study (https://clinicaltrials.gov/ct2/show/NCT03163511?term=NCT03163511&rank=1, accessed 20 November 2017). The primary efficacy endpoint is clinically relevant insulin production, as measured by C-peptide levels 6 months after implantation. Injectable insulin doses and hypoglycemia rates will also be evaluated as secondary endpoints. |
| September 7, 2017 | Boehringer Ingelheim announced a new Phase 2a study of BI 1467335 for diabetic retinopathy. This oral candidate, an inhibitor of amine oxidase, copper-containing 3 (AOC3), was acquired from Pharmaxis (Frenchs Forest, NSW, Australia) in May 2015. The double-blind safety/tolerability trial is expected to complete in November 2018 according to ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT03238963, accessed 20 November 2017), with primary completion in August 2018. The study aims to enroll 100 people with T1D or type 2 diabetes (T2D), HbA1c <10%, and non-proliferative diabetic retinopathy without diabetic macular edema (a score of 47–53 on the diabetic retinopathy severity scale [DRSS]). Participants will be randomized to once-daily BI 1467335 or placebo for 12 weeks, with an additional 120-week follow-up period. The primary endpoint is the proportion of participants with any ocular adverse events. Secondary endpoints include the proportion of patients with at least two-steps improvement in DRSS score, as well as the proportion of patients with non-ocular adverse events. BI 1467335 is also in Phase 2a development for non-alcoholic steatohepatitis (NASH), for which it has US Food and Drug Administration (FDA) Fast Track designation. |
| October 3, 2017 | Melior Pharmaceuticals (Exton, PA, USA) initiated a Phase 2b study of next-generation insulin sensitizer MLR-1023 (Lyn kinase activator) for T2D. The first participants were randomized to one of four arms: (i) a 25-mg daily tablet of MLR-1023; (ii) a 50-mg daily tablet; (iii) a 100-mg daily tablet; or (iv) placebo. The primary endpoint is change from baseline HbA1c after 12 weeks treatment. Melior and its partner Bukwang Pharmaceutical Company (Seoul, South Korea) aim to enroll 400 patients uncontrolled on metformin across 61 clinical sites in the US and Korea. According to ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT03279263?term=MLR-1023&rank=1, accessed 20 November 2017), the study is expected to complete in September 2019. Melior and Bukwang announced positive Phase 2a results on this T2D candidate in March 2016 (significant reductions in fasting plasma glucose and area under the curve in a mixed-meal tolerance test, lipid levels and weight loss trend in favor of MLR-1023 vs placebo) following FDA approval of an Investigational New Drug Application (IND) in March 2009. Earlier, preclinical research showed this agent's potential to more effectively lower blood glucose without inducing hypoglycemia or weight gain.5 |
| October 17, 2017 | Phase 2 results from a dose-ranging study (n = 632) of Novo Nordisk's oral semaglutide (the company released topline data in February 2015) were published in JAMA.6 Led by Professor Melanie Davies (University of Leicester, Leicester, UK), the study found that 90% of patients in the highest-dose (40 mg) group (n = 71) reached a target HbA1c <7% after 26 weeks. Among those in the lowest-dose (2.5 mg) group (n = 70), 44% reached HbA1c <7% compared with 28% of the placebo group (n = 71) and 93% of the group receiving semaglutide subcutaneously (n = 69). Of all five patient cohorts receiving oral semaglutide, 71% experienced ≥5% weight loss, ranging from 2.3 to 6.8 kg, although weight loss compared with placebo was only significant at the 10 mg dose and above (P < 0.001). All oral semaglutide doses gave significant HbA1c reductions: treatment differences compared with placebo were 0.4% for 2.5 mg semaglutide (P = 0.007) and 0.9%, 1.2%, 1.4%, and 1.6% for 5, 10, 20, and 40 mg semaglutide (all P < 0.001). These results indicate that oral semaglutide can be as efficacious as injectable semaglutide, although significantly larger doses are required due to the lower bioavailability of an agent when taken orally versus subcutaneously. Oral semaglutide is now well into the extensive Phase 3 PIONEER program, and the first of these studies (placebo-controlled PIONEER 1) is expected to complete in December 2017. |
| October 18, 2017 | An FDA Advisory Committee cast 16 votes in favor of approval for Novo Nordisk's once-weekly injectable formulation of the GLP-1 agonist semaglutide; one member of the committee abstained from voting, leading to a final tally of 16–0 from the 17-person panel. Although advisors unanimously voiced concerns regarding the retinopathy signal in SUSTAIN 6 (hazard ratio [HR] 1.76; 95% confidence interval [CI] 1.11–2.78),3 there was consensus that this risk should be addressed through a warning on the product label. All 17 voting members (endocrinologists, cardiologists, ophthalmologists, statisticians, and patient and consumer representatives) agreed that the benefits to semaglutide therapy far outweigh the possible risks. Retinopathy aside, panelists endorsed semaglutide's strong safety profile, comparable to that of existing GLP-1 agonists, and the greater ease of use of this compound. Novo Nordisk submitted a New Drug Application (NDA) for semaglutide in December 2016, and an FDA decision is expected by year end. |
| October 23, 2017 | AstraZeneca announced FDA approval of Bydureon BCise, a patient-friendly autoinjector for once-weekly GLP-1 agonist exenatide. The US launch is slated for the first quarter of 2018. Previously, the only available methods of administration for Bydureon were single-dose reconstitution kits and a multiuse dual-chamber pen, which still required a lengthy mixing and tapping process to create an aqueous solution prior to injection. The autoinjector comes with a hidden needle, and people can watch a plunger inside the device for confirmation that they have received the medication. Bydureon BCise uses the same microsphere technology underlying the reconstitution kits and dual-chamber pen, but will save time in the real world, and ultimately lessens the burden of injection with a more patient-friendly design. Data from two head-to-head trials will be featured on the new product label, one comparing Bydureon BCise with Byetta (AstraZeneca's twice-daily exenatide) and the other comparing Bydureon BCise with Januvia (Merck's [Kenilworth, NJ, USA] dipeptidyl peptidase [DPP]-4 inhibitor sitagliptin). The company announcement reports that overall the exenatide autoinjector was associated with mean HbA1c reductions up to 1.4% and with mean weight loss up to 1.4 kg after 28 weeks, whether taken as monotherapy or as an add-on to metformin, a sulfonylurea (SU), a thiazolidinedione (TZD), or any combination of SU/TZD. Clinicians will have to write prescriptions for Bydureon BCise specifically to get their patients the new autoinjector. The Bydureon autoinjector has also been accepted for active review by the European Medicines Agency (EMA). An EMA decision is expected in the last quarter of 2018. |
| November 2, 2017 | Novo Nordisk announced that the EMA has approved a label update for basal insulin product Tresiba (insulin degludec) to reflect reduced risk for severe hypoglycemia versus Sanofi's (Paris, France) Lantus (insulin glargine) based on the DEVOTE trial.7 This makes Tresiba the first diabetes product with a hypoglycemia benefit displayed on its label. In line with DEVOTE data, the European Union label now shows a 40% relative risk reduction for severe hypoglycemia (HR 0.60; 95% CI 0.48–0.76; P < 0.001) and a 53% relative risk reduction for nocturnal severe hypoglycemia (HR 0.47; 95% CI 0.31–0.73; P < 0.001) versus Lantus. This revision bolsters the SWITCH8, 9 results that are already on Tresiba's European product label (added early 2017). Novo Nordisk is expecting an FDA decision on a similar label update (hypoglycemia benefit based on both SWITCH and DEVOTE, being evaluated together by the agency) in the first quarter of 2018. |
