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doi: 10.1111/1753-0407.12126
Journal of Diabetes 6 (2014) 197–201
Journal of Diabetes NEWS The International Diabetes Federation’s 2013 World Diabetes Congress, Melbourne, Australia The International Diabetes Federation’s 2013 World Diabetes Congress (IDF 2013), held 2–6 December 2013 in Melbourne, Australia, brought together approximately 10 000 delegates from well over 100 countries. This impressive attendance figure made IDF 2013 the largest medical conference in Australian history. The meeting featured a substantial amount of new clinical data on diabetes drugs and devices, along with commentary on a number of big-picture topics in diabetes. In addition, the conference’s program featured daily jogs and even a theatrical play on barriers to patient initiation on injectable therapies. The International Diabetes Federation released its Sixth Diabetes Atlas a few weeks prior to the conference,1 which includes some remarkable statistics. The Atlas estimates the global diabetes patient population at 382 million, and projects that this will rise to 592 million by 2035. In addition it estimated the total diabetes care expenditures at US$548 billion in 2013, and projected this to rise to $627 billion in 2035.1 The fact that costs are projected to rise more slowly than prevalence is due to the fact that most new cases are expected to come from the developing world, where many patients may have trouble affording care. The facts in the Atlas underscored the enormous need for more effective therapies for diabetes patients.
Dr Hannele Yki-Järvinen (University of Helsinki, Helsinki, Finland) presented the full results of the EDITION II study on Sanofi’s U300 insulin glargine formulation, a more concentrated version of Sanofi’s Lantus (insulin glargine U100). EDITION II randomized 811 type 2 diabetes (T2D) patients on baseline treatment with basal insulin and at least one oral antidiabetic therapy (except for sulfonylureas) to treatment with either a U100 (Lantus) or U300 insulin glargine formulation. As was seen in the EDITION I study, the full results of which were presented at this year’s American Diabetes Association (ADA) Scientific Sessions,2 insulin glargine U300 was non-inferior to the U100 formulation in terms of lowering HbA1c (mean reduction of ∼0.6% from a mean baseline of 8.2%), and eight-point self-monitoring of blood glucose (SMBG) profiles were similar between the two groups. The main differentiating factor between the formulations was nocturnal hypoglycemia: between study Months 3 and 6, insulin glargine U300 led to a 23% decrease in confirmed or severe nocturnal hypoglycemia (P < 0.05). Interestingly, the U300 formulation led to a mean weight benefit of 1 kg (P < 0.05) relative to the U100 formulation. A major area of interest during IDF 2013 was the combination of basal insulin and glucagon-like peptide-1 (GLP-1) agonists, such as Novo Nordisk’s IDegLira, a fixed-ratio combination of Victoza (liraglutide) and Tresiba (insulin degludec). Results from the DUAL I
© 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Manu V. Venkat 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 Diabetes Close Up and Closer Look, periodicals that bring together news and insights in these areas. Each quarter, the Journal of Diabetes includes this News feature, in which Venkat and Close review the latest developments relevant to researchers and clinicians. Readers of Journal of Diabetes involved in the clinical care of patients with diabetes (including students and educators) may request a complimentary 1-year subscription to Close Concerns’ monthly newsletter, Diabetes Close Up (kelly.close@ closeconcerns.com).
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study, first presented at this year’s ADA,3 demonstrated an HbA1c reduction of 1.9% from a baseline of 8.3% after 26 weeks treatment with IDegLira. At IDF 2013, Dr Stephen Gough (University of Oxford, Oxford, UK) presented an analysis of the postprandial glucose reduction seen in DUAL I. Postprandial glucose levels for the entire 1663 patient study population were assessed through nine-point SMBG, and the postprandial glucose excursion was calculated as the difference between blood glucose readings before and 90 min after each meal. In addition, a subgroup of 260 patients underwent continuous glucose monitoring (CGM) at the initiation and end of the study. The SMBG data demonstrated that IDegLira provided significantly better glycemic control than insulin degludec alone (effect size of ∼10– 20 mg/dL), and comparable postprandial control to liraglutide. The CGM data were consistent with the SMBG findings: the average postprandial area under the curve (AUC) was significantly lower with IDegLira than with insulin degludec for all meals except lunch, for which the reduction did not reach statistical significance. Mean AUCs for IDegLira and liraglutide monotherapy were similar. On the GLP-1 agonist front, we saw new data presented by Dr Bo Ahrén (Lund University Diabetes Centre, Lund University, Lund, Sweden) on the flexible administration of Sanofi’s Lyxumia (lixisenatide) at either breakfast or during patients’ main meal of the day. The 198
24-week trial enrolled 451 T2D patients (mean HbA1c 8.0%, mean body mass index (BMI) 33 kg/m2, mean age 57 years) on background metformin therapy, categorizing them by their main meal of the day before randomizing them to prebreakfast or pre-main meal Lyxumia administration. After 24 weeks, there was no significant difference in the mean HbA1c reduction between the two groups (∼0.7%; P = 0.2664), and no significant differences in the groups’ mean reductions in body weight or fasting plasma glucose (FPG). The seven-point SMBG profiles demonstrated key differences between the groups, which stemmed from pharmacokinetics (the postprandial effect was diminished by the second and third meal postinjection). In terms of safety, there was no significant difference in gastrointestinal tolerability or hypoglycemia between the groups, and rates of hypoglycemia were low. Dr Xuejun Peng (Takeda, Osaka, Japan) presented the result of a Phase 2 study investigating the glycemic effects of Takeda’s GPR40 agonist fasiglifam (TAK-875) when used in combination with a dipeptidyl peptidase (DPP)-4 inhibitor (in this case, Merck’s Januvia [sitagliptin]). The 12-week randomized placebo-controlled doubleblind multicenter study randomized 360 treatment-naïve patients to fasiglifam 25 or 50 mg, either with or without a 100 mg sitagliptin dose. There was also a sitagliptin 100 mg monotherapy group as well as a placebo group, making for six groups in total.
Combination treatment (fasiglifam 50 mg + sitagliptin 100 mg) led to a mean HbA1c reduction of 1.2% from a baseline of 8.5%, significantly greater than the reduction seen with sitagliptin 100 mg monotherapy (0.6%) or fasiglifam 50 mg monotherapy (0.5%). Unfortunately, later in December, Takeda decided to halt the clinical testing of fasiglifam due to a liver safety signal (see Company Updates below). Although the majority of presentations at IDF 2013 focused on diabetes drugs and basic science, there were a few key presentations on diabetes devices and technology. Dr Roman Hovorka (University of Cambridge, Cambridge, UK) presented new data from a 21-day in-home, overnight, closed-loop, crossover study that randomized adolescents (n = 16) to sensoraugmented pump therapy for 21 days or overnight closed-loop for 21 days (with a washout period in between). The trial used an Abbott Laboratories (Abbott Park, IL, USA) Navigator CGM and a companion receiver, an insulin pump, and an ultraportable laptop running a control algorithm. The study attempted to simulate real-world conditions as much as possible. Patients connected to closed-loop at their convenience before bedtime (9:34 pm on average). Notably, the tighter control with closed-loop, which ended at 7:37 am on average, also improved open-loop control up until ∼12 pm the following day. There were no incidences of severe hypoglycemia or other adverse events during the study.
© 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Diabetes News
Journal of Diabetes NEWS
Dr Satish Garg (University of Colorado, Denver, CO, USA) presented encouraging results from a single-center pilot study comparing use of Sanofi’s iBGStar with the iPhone 4 (n = 50) to the Accu-Chek Nano (Hoffmann-La Roche, Basel, Switzerland; n = 50) in patients with type 1 diabetes (T1D). After 3 months, among the 88 study completers, HbA1c improved significantly in both groups, with a non-significant trend in favor of the iBGStar, a decline of 0.4% in the iBGStar group (baseline 8%; P = 0.008) compared with a 0.2% decline in the control group (baseline 7.7%; P = 0.04). In addition to data presentations, we heard some highly interesting thoughts, theories, and commentary on diabetes care from worldrenowned diabetologists. Dr Paul Zimmet (Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia) pointed out that the worldwide diabetes population is large enough to be the world’s thirdbiggest country. He noted, based on historical examples in China,
Cambodia, and Europe, that spikes in diabetes prevalence tend to follow a few decades after periods of famine. He suggested that this idea could be used to predict future diabetes “hot spots” based on recent periods of economic decline or famine. If you are interested in receiving the full Close Concerns report on the International Diabetes Federation’s 2013 World Diabetes Congress, please email Kelly Close (kelly [email protected]). References 1. International Diabetes Federation. IDF Diabetes Atlas, 6th edn. International Diabetes Federation, Brussels, 2013. 2. Riddle MC, Bolli GB, Ziemen MM, Muehlen-Bartmer I, Bizet F, Home PD. New insulin glargine formulation: Glucose control and hypoglycemia in people with type 2 diabetes using basal and mealtime insulin (EDITION I). In: Proceedings of the American Diabetes Association 73rd Annual Scientific Sessions. 2013. Available from: http://www .abstractsonline.com/plan/
ViewAbstract.aspx?mID=3217& sKey=0687e7c8-c97d-442b-92ecae505e051854&cKey=59c3dffc730d-4b5e-b02d-f9cf575941e6& mKey=%7B89918D6D-3018-4EA99D4F-711F98A7AE5D%7D (accessed 26 January 2014). 3. Buse JB, Gough SC, Woo VC et al. IDegLira, a novel fixed ratio combination of insulin degludec and liraglutide, is efficacious and safe in subjects with type 2 diabetes: A large, randomized Phase 3 trial (65-OR). In: Proceedings of the American Diabetes Association 73rd Annual Scientific Sessions. 2013. Available from: http://www.abstractsonline.com/ Plan/ViewAbstract.aspx?sKey =795037e5-ca6e-44a8-8b54cfb1400cd733&cKey=20b7a5463e26-40b8-a5eb578f9e982496&mKey=89918d6d3018-4ea9-9d4f-711f98a7ae5d (accessed 26 January 2014). 4. De Zeeuw D, Akizawa T, Audhya P et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med. 2013; 369: 2492–503. 5. Mitka M. Panel recommends easing restrictions on rosiglitazone despite concerns about cardiovascular safety. JAMA. 2013; 310: 246–7.
Company Updates
November 4:
The Juvenile Diabetes Research Foundation (JDRF) announced a partnership with Pfizer’s Centers for Therapeutic Innovation (CTI) to support the development and translation of promising T1D research. Together, Pfizer and the JDRF will choose four projects from the fields of immune tolerance, diabetic nephropathy, and β-cell health. Pfizer has extensive experience and biologics infrastructure that could potentially be applied to all three disease areas. A JDRF representative indicated that the partnership may eventually extend to additional candidates beyond the initial four. Pfizer will be responsible for the therapeutic candidate design, optimization, and preclinical and clinical testing.
November 7:
Bristol-Myers Squibb (BMS) announced that it would discontinue discovery-stage research in diabetes as part of a broader effort to “evolve” its research and development strategy towards areas with the “highest unmet need where the company can bring the greatest value”, such as immuno-oncology and virology. Management stated that it stood behind its diabetes products on the market and in late-stage clinical development (this turned out to not be the case; see December 19).
© 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
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Company Updates (Continued)
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November 9:
Data from Reata Pharmaceuticals’ discontinued Phase 3 BEACON trial for bardoxolone methyl (indicated for diabetic nephropathy) was published in the New England Journal of Medicine.4 In the trial, bardoxolone methyl led to a significant 83% increased risk of hospitalization for heart failure or death due to heart failure events (P < 0.001). There was also a significant increase in the secondary composite outcome of non-fatal myocardial infarction, non-fatal stroke, hospitalization for heart failure, or cardiovascular death (hazard ratio [HR] = 1.71; P < 0.001). The excess in adverse events for both measures occurred relatively early on, during the study’s initial weeks. Diabetic nephropathy remains a major area of unmet need for both the T1D and T2D populations.
November 12:
Ligand Pharmaceuticals announced the initiation of a Phase 1 study for its glucagon receptor (GCGR) antagonist LGD-6972 (ClinicalTrials.gov ID NCT01919684). The trial is a double-blind placebo-controlled single ascending dose study of 56 patients randomized to seven groups (six with individuals without diabetes and one with T2D patients). The primary goal is to determine the safety and tolerability of a single dose of LGD-6972.
November 14:
Eli Lilly and Company announced plans for US$700 million in investments in its insulin manufacturing capacity, in addition to the over US$1 billion it has invested in its insulin manufacturing facilities over the past year. The investment will go towards expanding active-ingredient insulin and delivery device manufacturing capacity in Puerto Rico and the company’s headquarters in Indianapolis (IN, USA), as well as towards facilities in France and China.
November 22:
Janssen-Cilag International announced that the European Commission (EC) approved the sodium–glucose cotransporter 2 (SGLT-2) inhibitor Invokana (canagliflozin), following a positive opinion delivered by the Committee for Medicinal Products for Human Use (CHMP) in September. Invokana was the second SGLT-2 inhibitor approved in Europe, following BMS and AstraZeneca’s (AZ) Forxiga (dapagliflozin), which was approved in 2012. Also on November 22, BMS and AZ announced that they had received a positive CHMP opinion for Xigduo, a fixed-dose combination of dapagliflozin and metformin hydrochloride.
November 25:
The US Food and Drug Administration (FDA) announced the removal of the major restrictions on the prescription and dispensation of GlaxoSmithKline’s Avandia (rosiglitazone), which previously had been subject to a risk evaluation and mitigation strategy (REMS) that limited patient access to the drug. This decision followed a re-adjudication of GlaxoSmithKline’s RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes) cardiovascular outcomes trial, which did not appear to conclusively indicate cardiovascular risk.5 The FDA stated that it would revise Avandia’s label (which had carried a cardiovascular risk warning) to reflect this new assessment.
November 26:
Echo Therapeutics reported initial results from a 32-patient four-center 24-h CE Mark (European conformity marking) of its non-invasive Symphony critical care continuous glucose monitor. The mean absolute relative difference versus a YSI glucose analyzer in the trial was 12.5% (n = 630), with 98% of points in Zone A of the continuous glucose-error grid.
December 3:
Sanofi released initial results from the Phase 3 EDITION III, IV, and JPI (Japan I) trials of its U300 insulin glargine formulation. All three trials met the primary endpoint of non-inferior HbA1c reductions at 6 months compared with Sanofi’s Lantus (insulin glargine U100).
© 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Diabetes News
Journal of Diabetes NEWS
Company Updates (Continued)
December 12:
The Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) of the US FDA voted 13–1 in favor of approval for BMS and AZ’s SGLT-2 inhibitor Forxiga (dapagliflozin). Coming into the advisory committee meeting, a non-significant imbalance in bladder cancers, a single case of possible drug-induced liver injury, and divergent clinical data on the drug’s cardiovascular effects were the major causes of potential concern listed by the FDA. Sponsor-provided evidence indicated that the bladder cancer and liver injury cases were unlikely to have all been caused by the study drug, and the panel voted 10–4 that the drug met the FDA’s cardiovascular safety requirements. The majority of the committee ultimately decided that the overall benefits of the drugs likely outweighed the possible risks.
December 12:
Johnson & Johnson announced that the US FDA issued a complete response letter for its fixed-dose combination (FDC) of the SGLT-2 inhibitor canagliflozin and immediate-release metformin. The agency requested additional information on whether the twice-daily dosing regimen of the FDC is comparable to the once-daily dosing of the approved canagliflozin monotherapy.
December 13:
BMS and AZ announced that they would withdraw Forxiga (dapagliflozin) from the market in Germany following a failure to reach an agreement with German authorities on the product’s pricing. The German Federal Joint Committee (G-BA) had ruled earlier in the year that Forxiga showed no added benefit over sulfonylureas: the ruling was not due to an assessment of the drug’s comparative effectiveness, but rather came because the drug’s clinical trial program did not meet the G-BA’s strict specifications.
December 19:
AZ announced that it would be acquiring BMS’ diabetes assets and business for US$2.7 billion, plus possible future milestone and royalty payments. Previously, the two companies had co-owned a shared diabetes portfolio. The move was part of BMS’ move away from primary care, towards specialty medicine areas such as immuno-oncology and virology. The transaction is expected to close in the first quarter of 2014 in most geographies. AZ management expressed enthusiasm for the deal, noting that AZ has a strong primary care presence as well as a strong presence in emerging economies, both of which are important arenas in the fight against diabetes.
December 20:
Eli Lilly and Company and Boehringer Ingelheim announced the regulatory submission of their insulin glargine formulation LY2963016 under the 505(b)(2) with the US FDA. The 505(b)(2) pathway allows for the inclusion of clinical data from an already-existing reference product, which (in this case) is Sanofi’s original insulin glargine Lantus. LY2963016 was submitted in Europe earlier in 2013.
December 27:
Takeda discontinued development of its potentially first-in-class free fatty acid receptor 1 (FFA1, or GPR40) agonist candidate TAK-875 (fasiglifam) due to unspecified liver safety concerns. The candidate had been in an extensive Phase 3 program involving at least 13 trials. TAK-875 held potential as a smarter insulin secretagog that could stimulate insulin secretion in a glucose-dependent manner and thus reduce the risk of hypoglycemia compared with non-glucose-dependent secretagogs such as the sulfonylurea class.
January 8:
The US FDA announced the approval of BMS and AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin) as monotherapy, as initial therapy with metformin, or as an add-on to other oral glucose-lowering agents, including metformin, pioglitazone, glimepiride, sitagliptin, and insulin. The agency will require six post-marketing studies, including the ongoing cardiovascular outcomes trial, trials in pediatric patients, and an animal study on dapagliflozin-induced urinary flow rate and urinary composition changes. The drug’s label indicates that the product should not be used in patients with moderate or severe renal impairment (estimated glomerular filtration rate
doi: 10.1111/1753-0407.12126
Journal of Diabetes 6 (2014) 197–201
Journal of Diabetes NEWS The International Diabetes Federation’s 2013 World Diabetes Congress, Melbourne, Australia The International Diabetes Federation’s 2013 World Diabetes Congress (IDF 2013), held 2–6 December 2013 in Melbourne, Australia, brought together approximately 10 000 delegates from well over 100 countries. This impressive attendance figure made IDF 2013 the largest medical conference in Australian history. The meeting featured a substantial amount of new clinical data on diabetes drugs and devices, along with commentary on a number of big-picture topics in diabetes. In addition, the conference’s program featured daily jogs and even a theatrical play on barriers to patient initiation on injectable therapies. The International Diabetes Federation released its Sixth Diabetes Atlas a few weeks prior to the conference,1 which includes some remarkable statistics. The Atlas estimates the global diabetes patient population at 382 million, and projects that this will rise to 592 million by 2035. In addition it estimated the total diabetes care expenditures at US$548 billion in 2013, and projected this to rise to $627 billion in 2035.1 The fact that costs are projected to rise more slowly than prevalence is due to the fact that most new cases are expected to come from the developing world, where many patients may have trouble affording care. The facts in the Atlas underscored the enormous need for more effective therapies for diabetes patients.
Dr Hannele Yki-Järvinen (University of Helsinki, Helsinki, Finland) presented the full results of the EDITION II study on Sanofi’s U300 insulin glargine formulation, a more concentrated version of Sanofi’s Lantus (insulin glargine U100). EDITION II randomized 811 type 2 diabetes (T2D) patients on baseline treatment with basal insulin and at least one oral antidiabetic therapy (except for sulfonylureas) to treatment with either a U100 (Lantus) or U300 insulin glargine formulation. As was seen in the EDITION I study, the full results of which were presented at this year’s American Diabetes Association (ADA) Scientific Sessions,2 insulin glargine U300 was non-inferior to the U100 formulation in terms of lowering HbA1c (mean reduction of ∼0.6% from a mean baseline of 8.2%), and eight-point self-monitoring of blood glucose (SMBG) profiles were similar between the two groups. The main differentiating factor between the formulations was nocturnal hypoglycemia: between study Months 3 and 6, insulin glargine U300 led to a 23% decrease in confirmed or severe nocturnal hypoglycemia (P < 0.05). Interestingly, the U300 formulation led to a mean weight benefit of 1 kg (P < 0.05) relative to the U100 formulation. A major area of interest during IDF 2013 was the combination of basal insulin and glucagon-like peptide-1 (GLP-1) agonists, such as Novo Nordisk’s IDegLira, a fixed-ratio combination of Victoza (liraglutide) and Tresiba (insulin degludec). Results from the DUAL I
© 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Manu V. Venkat 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 Diabetes Close Up and Closer Look, periodicals that bring together news and insights in these areas. Each quarter, the Journal of Diabetes includes this News feature, in which Venkat and Close review the latest developments relevant to researchers and clinicians. Readers of Journal of Diabetes involved in the clinical care of patients with diabetes (including students and educators) may request a complimentary 1-year subscription to Close Concerns’ monthly newsletter, Diabetes Close Up (kelly.close@ closeconcerns.com).
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Journal of Diabetes NEWS
study, first presented at this year’s ADA,3 demonstrated an HbA1c reduction of 1.9% from a baseline of 8.3% after 26 weeks treatment with IDegLira. At IDF 2013, Dr Stephen Gough (University of Oxford, Oxford, UK) presented an analysis of the postprandial glucose reduction seen in DUAL I. Postprandial glucose levels for the entire 1663 patient study population were assessed through nine-point SMBG, and the postprandial glucose excursion was calculated as the difference between blood glucose readings before and 90 min after each meal. In addition, a subgroup of 260 patients underwent continuous glucose monitoring (CGM) at the initiation and end of the study. The SMBG data demonstrated that IDegLira provided significantly better glycemic control than insulin degludec alone (effect size of ∼10– 20 mg/dL), and comparable postprandial control to liraglutide. The CGM data were consistent with the SMBG findings: the average postprandial area under the curve (AUC) was significantly lower with IDegLira than with insulin degludec for all meals except lunch, for which the reduction did not reach statistical significance. Mean AUCs for IDegLira and liraglutide monotherapy were similar. On the GLP-1 agonist front, we saw new data presented by Dr Bo Ahrén (Lund University Diabetes Centre, Lund University, Lund, Sweden) on the flexible administration of Sanofi’s Lyxumia (lixisenatide) at either breakfast or during patients’ main meal of the day. The 198
24-week trial enrolled 451 T2D patients (mean HbA1c 8.0%, mean body mass index (BMI) 33 kg/m2, mean age 57 years) on background metformin therapy, categorizing them by their main meal of the day before randomizing them to prebreakfast or pre-main meal Lyxumia administration. After 24 weeks, there was no significant difference in the mean HbA1c reduction between the two groups (∼0.7%; P = 0.2664), and no significant differences in the groups’ mean reductions in body weight or fasting plasma glucose (FPG). The seven-point SMBG profiles demonstrated key differences between the groups, which stemmed from pharmacokinetics (the postprandial effect was diminished by the second and third meal postinjection). In terms of safety, there was no significant difference in gastrointestinal tolerability or hypoglycemia between the groups, and rates of hypoglycemia were low. Dr Xuejun Peng (Takeda, Osaka, Japan) presented the result of a Phase 2 study investigating the glycemic effects of Takeda’s GPR40 agonist fasiglifam (TAK-875) when used in combination with a dipeptidyl peptidase (DPP)-4 inhibitor (in this case, Merck’s Januvia [sitagliptin]). The 12-week randomized placebo-controlled doubleblind multicenter study randomized 360 treatment-naïve patients to fasiglifam 25 or 50 mg, either with or without a 100 mg sitagliptin dose. There was also a sitagliptin 100 mg monotherapy group as well as a placebo group, making for six groups in total.
Combination treatment (fasiglifam 50 mg + sitagliptin 100 mg) led to a mean HbA1c reduction of 1.2% from a baseline of 8.5%, significantly greater than the reduction seen with sitagliptin 100 mg monotherapy (0.6%) or fasiglifam 50 mg monotherapy (0.5%). Unfortunately, later in December, Takeda decided to halt the clinical testing of fasiglifam due to a liver safety signal (see Company Updates below). Although the majority of presentations at IDF 2013 focused on diabetes drugs and basic science, there were a few key presentations on diabetes devices and technology. Dr Roman Hovorka (University of Cambridge, Cambridge, UK) presented new data from a 21-day in-home, overnight, closed-loop, crossover study that randomized adolescents (n = 16) to sensoraugmented pump therapy for 21 days or overnight closed-loop for 21 days (with a washout period in between). The trial used an Abbott Laboratories (Abbott Park, IL, USA) Navigator CGM and a companion receiver, an insulin pump, and an ultraportable laptop running a control algorithm. The study attempted to simulate real-world conditions as much as possible. Patients connected to closed-loop at their convenience before bedtime (9:34 pm on average). Notably, the tighter control with closed-loop, which ended at 7:37 am on average, also improved open-loop control up until ∼12 pm the following day. There were no incidences of severe hypoglycemia or other adverse events during the study.
© 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Diabetes News
Journal of Diabetes NEWS
Dr Satish Garg (University of Colorado, Denver, CO, USA) presented encouraging results from a single-center pilot study comparing use of Sanofi’s iBGStar with the iPhone 4 (n = 50) to the Accu-Chek Nano (Hoffmann-La Roche, Basel, Switzerland; n = 50) in patients with type 1 diabetes (T1D). After 3 months, among the 88 study completers, HbA1c improved significantly in both groups, with a non-significant trend in favor of the iBGStar, a decline of 0.4% in the iBGStar group (baseline 8%; P = 0.008) compared with a 0.2% decline in the control group (baseline 7.7%; P = 0.04). In addition to data presentations, we heard some highly interesting thoughts, theories, and commentary on diabetes care from worldrenowned diabetologists. Dr Paul Zimmet (Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia) pointed out that the worldwide diabetes population is large enough to be the world’s thirdbiggest country. He noted, based on historical examples in China,
Cambodia, and Europe, that spikes in diabetes prevalence tend to follow a few decades after periods of famine. He suggested that this idea could be used to predict future diabetes “hot spots” based on recent periods of economic decline or famine. If you are interested in receiving the full Close Concerns report on the International Diabetes Federation’s 2013 World Diabetes Congress, please email Kelly Close (kelly [email protected]). References 1. International Diabetes Federation. IDF Diabetes Atlas, 6th edn. International Diabetes Federation, Brussels, 2013. 2. Riddle MC, Bolli GB, Ziemen MM, Muehlen-Bartmer I, Bizet F, Home PD. New insulin glargine formulation: Glucose control and hypoglycemia in people with type 2 diabetes using basal and mealtime insulin (EDITION I). In: Proceedings of the American Diabetes Association 73rd Annual Scientific Sessions. 2013. Available from: http://www .abstractsonline.com/plan/
ViewAbstract.aspx?mID=3217& sKey=0687e7c8-c97d-442b-92ecae505e051854&cKey=59c3dffc730d-4b5e-b02d-f9cf575941e6& mKey=%7B89918D6D-3018-4EA99D4F-711F98A7AE5D%7D (accessed 26 January 2014). 3. Buse JB, Gough SC, Woo VC et al. IDegLira, a novel fixed ratio combination of insulin degludec and liraglutide, is efficacious and safe in subjects with type 2 diabetes: A large, randomized Phase 3 trial (65-OR). In: Proceedings of the American Diabetes Association 73rd Annual Scientific Sessions. 2013. Available from: http://www.abstractsonline.com/ Plan/ViewAbstract.aspx?sKey =795037e5-ca6e-44a8-8b54cfb1400cd733&cKey=20b7a5463e26-40b8-a5eb578f9e982496&mKey=89918d6d3018-4ea9-9d4f-711f98a7ae5d (accessed 26 January 2014). 4. De Zeeuw D, Akizawa T, Audhya P et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease. N Engl J Med. 2013; 369: 2492–503. 5. Mitka M. Panel recommends easing restrictions on rosiglitazone despite concerns about cardiovascular safety. JAMA. 2013; 310: 246–7.
Company Updates
November 4:
The Juvenile Diabetes Research Foundation (JDRF) announced a partnership with Pfizer’s Centers for Therapeutic Innovation (CTI) to support the development and translation of promising T1D research. Together, Pfizer and the JDRF will choose four projects from the fields of immune tolerance, diabetic nephropathy, and β-cell health. Pfizer has extensive experience and biologics infrastructure that could potentially be applied to all three disease areas. A JDRF representative indicated that the partnership may eventually extend to additional candidates beyond the initial four. Pfizer will be responsible for the therapeutic candidate design, optimization, and preclinical and clinical testing.
November 7:
Bristol-Myers Squibb (BMS) announced that it would discontinue discovery-stage research in diabetes as part of a broader effort to “evolve” its research and development strategy towards areas with the “highest unmet need where the company can bring the greatest value”, such as immuno-oncology and virology. Management stated that it stood behind its diabetes products on the market and in late-stage clinical development (this turned out to not be the case; see December 19).
© 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
199
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Journal of Diabetes NEWS
Company Updates (Continued)
200
November 9:
Data from Reata Pharmaceuticals’ discontinued Phase 3 BEACON trial for bardoxolone methyl (indicated for diabetic nephropathy) was published in the New England Journal of Medicine.4 In the trial, bardoxolone methyl led to a significant 83% increased risk of hospitalization for heart failure or death due to heart failure events (P < 0.001). There was also a significant increase in the secondary composite outcome of non-fatal myocardial infarction, non-fatal stroke, hospitalization for heart failure, or cardiovascular death (hazard ratio [HR] = 1.71; P < 0.001). The excess in adverse events for both measures occurred relatively early on, during the study’s initial weeks. Diabetic nephropathy remains a major area of unmet need for both the T1D and T2D populations.
November 12:
Ligand Pharmaceuticals announced the initiation of a Phase 1 study for its glucagon receptor (GCGR) antagonist LGD-6972 (ClinicalTrials.gov ID NCT01919684). The trial is a double-blind placebo-controlled single ascending dose study of 56 patients randomized to seven groups (six with individuals without diabetes and one with T2D patients). The primary goal is to determine the safety and tolerability of a single dose of LGD-6972.
November 14:
Eli Lilly and Company announced plans for US$700 million in investments in its insulin manufacturing capacity, in addition to the over US$1 billion it has invested in its insulin manufacturing facilities over the past year. The investment will go towards expanding active-ingredient insulin and delivery device manufacturing capacity in Puerto Rico and the company’s headquarters in Indianapolis (IN, USA), as well as towards facilities in France and China.
November 22:
Janssen-Cilag International announced that the European Commission (EC) approved the sodium–glucose cotransporter 2 (SGLT-2) inhibitor Invokana (canagliflozin), following a positive opinion delivered by the Committee for Medicinal Products for Human Use (CHMP) in September. Invokana was the second SGLT-2 inhibitor approved in Europe, following BMS and AstraZeneca’s (AZ) Forxiga (dapagliflozin), which was approved in 2012. Also on November 22, BMS and AZ announced that they had received a positive CHMP opinion for Xigduo, a fixed-dose combination of dapagliflozin and metformin hydrochloride.
November 25:
The US Food and Drug Administration (FDA) announced the removal of the major restrictions on the prescription and dispensation of GlaxoSmithKline’s Avandia (rosiglitazone), which previously had been subject to a risk evaluation and mitigation strategy (REMS) that limited patient access to the drug. This decision followed a re-adjudication of GlaxoSmithKline’s RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes) cardiovascular outcomes trial, which did not appear to conclusively indicate cardiovascular risk.5 The FDA stated that it would revise Avandia’s label (which had carried a cardiovascular risk warning) to reflect this new assessment.
November 26:
Echo Therapeutics reported initial results from a 32-patient four-center 24-h CE Mark (European conformity marking) of its non-invasive Symphony critical care continuous glucose monitor. The mean absolute relative difference versus a YSI glucose analyzer in the trial was 12.5% (n = 630), with 98% of points in Zone A of the continuous glucose-error grid.
December 3:
Sanofi released initial results from the Phase 3 EDITION III, IV, and JPI (Japan I) trials of its U300 insulin glargine formulation. All three trials met the primary endpoint of non-inferior HbA1c reductions at 6 months compared with Sanofi’s Lantus (insulin glargine U100).
© 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd
Diabetes News
Journal of Diabetes NEWS
Company Updates (Continued)
December 12:
The Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) of the US FDA voted 13–1 in favor of approval for BMS and AZ’s SGLT-2 inhibitor Forxiga (dapagliflozin). Coming into the advisory committee meeting, a non-significant imbalance in bladder cancers, a single case of possible drug-induced liver injury, and divergent clinical data on the drug’s cardiovascular effects were the major causes of potential concern listed by the FDA. Sponsor-provided evidence indicated that the bladder cancer and liver injury cases were unlikely to have all been caused by the study drug, and the panel voted 10–4 that the drug met the FDA’s cardiovascular safety requirements. The majority of the committee ultimately decided that the overall benefits of the drugs likely outweighed the possible risks.
December 12:
Johnson & Johnson announced that the US FDA issued a complete response letter for its fixed-dose combination (FDC) of the SGLT-2 inhibitor canagliflozin and immediate-release metformin. The agency requested additional information on whether the twice-daily dosing regimen of the FDC is comparable to the once-daily dosing of the approved canagliflozin monotherapy.
December 13:
BMS and AZ announced that they would withdraw Forxiga (dapagliflozin) from the market in Germany following a failure to reach an agreement with German authorities on the product’s pricing. The German Federal Joint Committee (G-BA) had ruled earlier in the year that Forxiga showed no added benefit over sulfonylureas: the ruling was not due to an assessment of the drug’s comparative effectiveness, but rather came because the drug’s clinical trial program did not meet the G-BA’s strict specifications.
December 19:
AZ announced that it would be acquiring BMS’ diabetes assets and business for US$2.7 billion, plus possible future milestone and royalty payments. Previously, the two companies had co-owned a shared diabetes portfolio. The move was part of BMS’ move away from primary care, towards specialty medicine areas such as immuno-oncology and virology. The transaction is expected to close in the first quarter of 2014 in most geographies. AZ management expressed enthusiasm for the deal, noting that AZ has a strong primary care presence as well as a strong presence in emerging economies, both of which are important arenas in the fight against diabetes.
December 20:
Eli Lilly and Company and Boehringer Ingelheim announced the regulatory submission of their insulin glargine formulation LY2963016 under the 505(b)(2) with the US FDA. The 505(b)(2) pathway allows for the inclusion of clinical data from an already-existing reference product, which (in this case) is Sanofi’s original insulin glargine Lantus. LY2963016 was submitted in Europe earlier in 2013.
December 27:
Takeda discontinued development of its potentially first-in-class free fatty acid receptor 1 (FFA1, or GPR40) agonist candidate TAK-875 (fasiglifam) due to unspecified liver safety concerns. The candidate had been in an extensive Phase 3 program involving at least 13 trials. TAK-875 held potential as a smarter insulin secretagog that could stimulate insulin secretion in a glucose-dependent manner and thus reduce the risk of hypoglycemia compared with non-glucose-dependent secretagogs such as the sulfonylurea class.
January 8:
The US FDA announced the approval of BMS and AZ’s SGLT-2 inhibitor Farxiga (dapagliflozin) as monotherapy, as initial therapy with metformin, or as an add-on to other oral glucose-lowering agents, including metformin, pioglitazone, glimepiride, sitagliptin, and insulin. The agency will require six post-marketing studies, including the ongoing cardiovascular outcomes trial, trials in pediatric patients, and an animal study on dapagliflozin-induced urinary flow rate and urinary composition changes. The drug’s label indicates that the product should not be used in patients with moderate or severe renal impairment (estimated glomerular filtration rate
