Codelivery of TGFß and Cox2 siRNA inhibits HCC by promoting T-cell penetration into the tumor and improves response to Immune Checkpoint Inhibitors.

Upregulation of TGFß and Cox2 in the tumor microenvironment results in blockade of T-cell penetration into the tumor. Without access to tumor antigens, the T-cell response will not benefit from administration of the immune checkpoint antibodies. We created an intravenous polypeptide nanoparticle that can deliver two siRNAs (silencing TGFß and Cox2). Systemic administration in mice, bearing a syngeneic orthotopic hepatocellular carcinoma (HCC), delivers the siRNAs to various cells in the liver, and significantly reduces the tumor. At 2 mg/kg (BIW) the nanoparticle demonstrated a single agent action and induced tumor growth inhibition to undetectable levels after five doses. Reducing the siRNAs to 1mg/kg BIW demonstrated greater inhibition in the presence of PD-L1 mAbs. After only three doses BIW, we could still recover a smaller tumor and, in tumor sections, showed an increase in penetration of CD4+ and CD8+ T-cells deeper into the remaining tumor that was not evident in animals treated with non-silencing siRNA. The combination of TGFß and Cox2 siRNA co-administered in a polypeptide nanoparticle can act as a novel therapeutic alone against HCC and may augment the activity of the immune checkpoint antibodies. Silencing TGFß and Cox2 converts an immune excluded (cold) tumor into a T-cell inflamed (hot) tumor.

Long-term efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes: pooled 52-week outcomes from the DEPICT-1 and -2 studies.

AIM: To evaluate the efficacy and safety of adjunct dapagliflozin therapy in patients with type 1 diabetes (T1D). MATERIALS AND METHODS: DEPICT-1 and -2 were randomized, double-blind, parallel-group, 24-week studies, with 28-week extension periods. Adults with T1D and HbA1c 7.5%-10.5% were randomized (1:1:1) to receive dapagliflozin 5 mg, 10 mg or placebo. The short- and long-term efficacy and safety of dapagliflozin were examined in an exploratory pooled analysis of both studies. RESULTS: Efficacy analyses included 530, 529 and 532 and safety analysis included 548, 566 and 532 patients in the dapagliflozin 5 mg, 10 mg and placebo groups, respectively. Baseline characteristics were similar between treatment groups. At week 24, reductions were seen with dapagliflozin 5 and 10 mg compared with placebo in HbA1c (-0.40%, -0.43% vs. 0.00%) and body weight (-2.45, -2.91 vs. 0.11 kg). HbA1c and body weight reductions versus placebo were also seen after 52 weeks of treatment. There was no imbalance in occurrence of severe hypoglycaemic events between groups. The proportion of patients experiencing definite diabetic ketoacidosis (DKA) was higher with dapagliflozin 5 mg (4.0%) and 10 mg (3.5%) compared with placebo (1.1%) over 52 weeks; most events were of mild or moderate severity, and all resolved with treatment. CONCLUSIONS: Over 52 weeks, dapagliflozin provided glycaemic and weight benefits, with no increased frequency of severe hypoglycaemia compared with placebo. More DKA events were reported with dapagliflozin than placebo, highlighting the importance of appropriate patient selection, education and risk-mitigation strategies.

Dapagliflozin effects on haematocrit, red blood cell count and reticulocytes in insulin-treated patients with type 2 diabetes.

Recent studies have shown that high-risk patients with type 2 diabetes mellitus (T2DM) treated with sodium glucose cotransporter 2 (SGLT2) inhibitors have improved cardiovascular (CV) outcomes. In an exploratory analysis of data from the EMPA-REG study, elevations in haematocrit were shown to be strongly associated with beneficial CV effects. As insulin treatment has been shown to be antinatriuretic, with an associated increase in extracellular fluid volume, it is important to confirm whether haematocrit increase is maintained with concomitant insulin therapy. Here, we investigate the effect of the SGLT2 inhibitor dapagliflozin on haematocrit, red blood cell (RBC) counts and reticulocyte levels in high-risk patients with T2DM receiving insulin. A 24-week, double-blinded, randomised, placebo-controlled trial (ClinicalTrials.gov: NCT00673231) was reported previously with extension periods of 24 and 56 weeks (total of 104 weeks). Patients receiving insulin were randomised 1:1:1:1 to placebo or dapagliflozin at 2.5, 5 or 10 mg. Haematocrit, RBC and reticulocyte measurements were conducted during this study, and a longitudinal repeated-measures analysis was performed here to examine change from baseline during treatment. Dapagliflozin treatment in combination with insulin resulted in a dose-dependent increase in haematocrit levels and RBCs over a 104 week period. There was a short-term increase in reticulocyte levels at the start of treatment, which dropped to below baseline after 8 weeks. SGLT2 inhibition with dapagliflozin leads to a sustained increase in haematocrit in patients receiving chronic insulin treatment.

Effect of dapagliflozin as an adjunct to insulin over 52 weeks in individuals with type 1 diabetes: post-hoc renal analysis of the DEPICT randomised controlled trials.

BACKGROUND: The DEPICT-1 and DEPICT-2 studies showed that dapagliflozin as an adjunct to insulin in individuals with inadequately controlled type 1 diabetes improved glycaemic control and bodyweight, without increase in risk of hypoglycaemia. We aimed to determine the effect of dapagliflozin on urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) using pooled data from the DEPICT studies. METHODS: In this post-hoc analysis, we used data pooled from both DEPICT studies (DEPICT-1 ran from Nov 11, 2014, to Aug 25, 2017; DEPICT-2 ran from July 8, 2015, to April 18, 2018), in which participants were aged 18-75 years, with inadequately controlled type 1 diabetes and with a baseline UACR of at least 30 mg/g. In the DEPICT studies, participants were randomly assigned (1:1:1) to receive dapagliflozin (5 mg or 10 mg) or placebo all plus insulin, for 24 weeks, with a 28-week long-term extension (ie, 52 weeks in total). In this post-hoc analysis, we assessed the percentage change from baseline in UACR and in eGFR, up to 52 weeks. UACR, eGFR, and safety were assessed in all eligible participants who had received at least one dose of study drug. HbA1c, bodyweight, and systolic blood pressure were assessed in all participants who received at least one dose of study drug during the first 24-week period, and who had a baseline and any post-baseline assessment for that parameter. The DEPICT trials were registered with ClinicalTrials.gov, NCT02268214 (DEPICT-1), NCT02460978 (DEPICT-2), and are now complete. RESULTS: 251 participants with albuminuria at baseline were included in this post-hoc analysis; of whom 80 (32%) had been randomly assigned to dapagliflozin 5 mg, 84 (33%) to dapagliflozin 10 mg, and 87 (35%) to placebo. Compared with placebo, treatment with both dapagliflozin doses improved UACR over 52 weeks. At week 52, mean difference in change from baseline versus placebo in UACR was -13·3% (95% CI -37·2 to 19·8) for dapagliflozin 5 mg and -31·1% (-49·9 to -5·2) for dapagliflozin 10 mg. No notable change from baseline was seen in eGFR, with a mean difference in change from baseline versus placebo of 3·27 mL/min per 1·73 m2 (95% CI -0·92 to 7·45) for dapagliflozin 5 mg and 2·12 mL/min per 1·73 m2 (-2·03 to 6·27) for dapagliflozin 10 mg. Similar proportions of participants in each treatment group had adverse events and serious adverse events, including hypoglycaemia and diabetic ketoacidosis; no new safety signals were identified in this population. INTERPRETATION: Treatment with dapagliflozin resulted in UACR reduction, which might provide renoprotective benefits in individuals with type 1 diabetes and albuminuria. Dedicated prospective studies are needed to confirm these findings as prespecified endpoints. FUNDING: AstraZeneca.

Benefit/risk profile of dapagliflozin 5 mg in the DEPICT-1 and -2 trials in individuals with type 1 diabetes and body mass index ≥27 kg/m2.

AIM: The DEPICT-1 and -2 studies (NCT02268214, NCT02460978) evaluated the efficacy and safety of dapagliflozin in individuals with type 1 diabetes who were receiving intensive insulin therapy. The DEPICT-1 and -2 studies (NCT02268214, NCT02460978) evaluated the efficacy and safety of dapagliflozin in individuals with type 1 diabetes. This post-hoc study investigated the safety and efficacy of dapagliflozin in individuals with BMI ≥27 kg/m2 to assess if the benefit/risk ratio associated with dapagliflozin treatment can be further improved than that observed in the overall DEPICT population. METHODS: Changes in glycated haemoglobin (HbA1c) and body weight, percentage change in daily insulin dose and proportion of participants achieving HbA1c reduction ≥0.5% without severe hypoglycaemia were evaluated at weeks 24 and 52. Changes in mean interstitial glucose, mean amplitude of glycaemic excursions and time in target glycaemic range were evaluated at week 24. Safety was assessed until week 56. RESULTS: Week-52 adjusted mean (SE) change from baseline for HbA1c was -0.26% (0.05) with dapagliflozin versus +0.08% (0.05) with placebo and for body weight was -2.74 kg (0.25) with dapagliflozin versus +0.81 kg (0.26) with placebo. Mean (SE) percentage change in daily insulin dose was -10.5% (1.23) with dapagliflozin versus -1.4% (1.36) with placebo. Time spent in target glycaemic range increased by 2.2 h/day versus placebo. Dapagliflozin was well tolerated, with fewer participants experiencing diabetic ketoacidosis (dapagliflozin, 1.7%; placebo, 1.0%) than dapagliflozin 5 mg receiving participants in the pooled DEPICT populations. CONCLUSIONS: Compared with the pooled DEPICT population, the benefit/risk profile of adjunct dapagliflozin therapy was more favourable in individuals with type 1 diabetes with body mass index ≥27 kg/m2 because of the reduced risk of diabetic ketoacidosis in this population.

Developmental and transcriptional responses of maize to drought stress under field conditions.

Drought is a common abiotic stress which significantly limits global crop productivity. Maize is an important staple crop and its yield is determined by successful development of the female inflorescence, the ear. We investigated drought stress responses across several developmental stages of the maize B73 inbred line under field conditions. Drought suppressed plant growth, but had little impact on progression through developmental stages. While ear growth was suppressed by drought, the process of spikelet initiation was not significantly affected. Tassel growth was reduced to a lesser extent compared to the observed reduction in ear growth under stress. Parallel RNA-seq profiling of leaves, ears, and tassels at several developmental stages revealed tissue-specific differences in response to drought stress. High temperature fluctuation was an additional environmental factor that also likely influenced gene expression patterns in the field. Drought induced significant transcriptional changes in leaves and ears but only minor changes in the tassel. Additionally, more genes were drought responsive in ears compared to leaves over the course of drought treatment. Genes that control DNA replication, cell cycle, and cell division were significantly down-regulated in stressed ears, which was consistent with inhibition of ear growth under drought. Inflorescence meristem genes were affected by drought to a lesser degree which was consistent with the minimal impact of drought on spikelet initiation. In contrast, genes that are involved in floret and ovule development were sensitive to stress, which is consistent with the detrimental effect of drought on gynoecium development and kernel set.

Glucose Variables in Type 1 Diabetes Studies With Dapagliflozin: Pooled Analysis of Continuous Glucose Monitoring Data From DEPICT-1 and -2.

OBJECTIVE: This pooled analysis assessed continuous glucose monitoring (CGM) in patients with inadequately controlled type 1 diabetes (HbA1c ≥7.7 to ≤11.0% [≥61 to ≤97 mmol/mol]) who received dapagliflozin as an adjunct to adjustable insulin. RESEARCH DESIGN AND METHODS: CGM data were pooled from two 24-week, double-blind, randomized, phase 3 studies: Dapagliflozin Evaluation in Patients with Inadequately Controlled Type 1 Diabetes (DEPICT-1 and DEPICT-2). These studies comprised 1,591 patients receiving dapagliflozin 5 mg (n = 530), dapagliflozin 10 mg (n = 529), or placebo (n = 532). RESULTS: Baseline characteristics were balanced between treatment groups. Patients receiving dapagliflozin 5 mg or 10 mg both spent more time with blood glucose in the range >3.9 to ≤10.0 mmol/L (>70 to ≤180 mg/dL) over 24 h than those receiving the placebo. The adjusted mean (SE) change from baseline at week 24 was 6.48% (0.60) with dapagliflozin 5 mg, 8.08% (0.60) with dapagliflozin 10 mg, and -2.59% (0.61) with placebo. At week 24, the mean amplitude of glucose excursion over 24 h, mean 24-h glucose values, and postprandial glucose values were also improved in patients receiving dapagliflozin over those receiving placebo. No marked differences were found at week 24 between dapagliflozin 5 or 10 mg and placebo in the percentage of glucose values ≤3.9 mmol/L (≤70 mg/dL) or ≤3.0 mmol/L (≤54 mg/dL) over 24 h, or in nocturnal (0000-0559 h) glucose values ≤3.9 mmol/L (≤70 mg/dL). CONCLUSIONS: In patients with type 1 diabetes, treatment with dapagliflozin over 24 weeks improved time in range, mean glucose, and glycemic variability without increasing the time spent in the range indicating hypoglycemia.

Efficacy and Safety of Dapagliflozin in Patients With Inadequately Controlled Type 1 Diabetes: The DEPICT-1 52-Week Study.

OBJECTIVE: This study evaluated the long-term safety and efficacy of dapagliflozin as an adjunct to adjustable insulin in patients with type 1 diabetes and inadequate glycemic control. RESEARCH DESIGN AND METHODS: DEPICT-1 (Dapagliflozin Evaluation in Patients With Inadequately Controlled Type 1 Diabetes) was a randomized (1:1:1), double-blind, placebo-controlled phase 3 study of dapagliflozin 5 mg and 10 mg in patients with type 1 diabetes (HbA1c 7.5-10.5% [58-91 mmol/mol]) (NCT02268214). The results of the 52-week study, consisting of the 24-week short-term and 28-week extension period, are reported here. RESULTS: Of the 833 patients randomized into the study, 708 (85%) completed the 52-week study. Over 52 weeks, dapagliflozin 5 mg and 10 mg led to clinically significant reductions in HbA1c (difference vs. placebo [95% CI] -0.33% [-0.49, -0.17] [-3.6 mmol/mol (-5.4, -1.9)] and -0.36% [-0.53, -0.20] [-3.9 mmol/mol (-5.8, -2.2)], respectively) and body weight (difference vs. placebo [95% CI] -2.95% [-3.83, -2.06] and -4.54% [-5.40, -3.66], respectively). Serious adverse events were reported in 13.4%, 13.5%, and 11.5% of patients in the dapagliflozin 5 mg, 10 mg, and placebo groups, respectively. Although hypoglycemia events were comparable across treatment groups, more patients in the dapagliflozin groups had events adjudicated as definite diabetic ketoacidosis (DKA; 4.0%, 3.4%, and 1.9% in dapagliflozin 5 mg, 10 mg, and placebo groups, respectively). CONCLUSIONS: Over 52 weeks, dapagliflozin led to improvements in glycemic control and weight loss in patients with type 1 diabetes, while increasing the risk of DKA.

Simultaneous silencing of TGF-ß1 and COX-2 reduces human skin hypertrophic scar through activation of fibroblast apoptosis.

Excessive skin scars due to elective operations or trauma represent a challenging clinical problem. Pathophysiology of hypertrophic scars entails a prolonged inflammatory and proliferative phase of wound healing. Over expression of TGF-ß1 and COX-2 play key regulatory roles of the aberrant fibrogenic responses and proinflammatory mediators. When we silenced TGF-ß1 and COX-2 expression simultaneously in primary human fibroblasts, a marked increase in the apoptotic cell population occurred in contrast to those only treated with either TGF-ß1 or COX-2 siRNA alone. Furthermore, using human hypertrophic scar and skin graft implant models in mice, we observed significant size reductions of the implanted tissues following intra-scar administration of TGF-ß1/COX-2 specific siRNA combination packaged with Histidine Lysine Polymer (HKP). Gene expression analyses of those treated tissues revealed silencing of the target gene along with down regulations of pro-fibrotic factors such as α-SMA, hydroxyproline acid, Collagen 1 and Collagen 3. Using TUNEL assay detection, we found that the human fibroblasts in the implanted tissues treated with the TGF-ß1/COX-2siRNAs combination exhibited significant apoptotic activity. Therefore we conclude that a synergistic effect of the TGF-ß1/COX-2siRNAs combination contributed to the size reductions of the hypertrophic scar implants, through activation of fibroblast apoptosis and re-balancing between scar tissue deposition and degradation.

Map Sensitivity vs. Map Dependency: A Case Study of Subway Maps' Impact on Passenger Route Choices in Washington DC.

This paper addresses the key assumption in behavioral and transportation planning literature that, when people use a transit system more frequently, they become less dependent on and less sensitive to transit maps in their decision-making. Therefore, according to this assumption, map changes are much less impactful to travel decisions of frequent riders than to that of first-time or new passengers. This assumption-though never empirically validated-has been the major hurdle for transit maps to becoming a planning tool to change passengers' behavior. This paper examines this assumption using the Washington DC metro map as a case study by conducting a route choice experiment between 30 Origin-Destination (O-D) pairs on seven metro map designs. The experiment targets two types of passengers: frequent metro riders through advertisements on a free daily newspaper available at DC metro stations, and general residents in the Washington metropolitan area through Amazon Mechanical Turk, an online crowdsourcing platform. A total of 255 and 371 participants made 2024 and 2960 route choices in the respective experiments. The results show that frequent passengers are in fact more sensitive to subtle changes in map design than general residents who are less likely to be familiar with the metro map and therefore unaffected by map changes presented in the alternative designs. The work disproves the aforementioned assumption and further validates metro maps as an effective planning tool in transit systems.

Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial.

BACKGROUND: Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor approved for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of dapagliflozin as an add-on to adjustable insulin in patients with inadequately controlled type 1 diabetes. METHODS: DEPICT-1 was a double-blind, randomised, parallel-controlled, three-arm, phase 3, multicentre study done at 143 sites in 17 countries. Eligible patients were aged 18-75 years and had inadequately controlled type 1 diabetes (HbA1c between ≥7·7% and ≤11·0% [≥61·0 mmol/mol and ≤97·0 mmol/mol]) and had been prescribed insulin for at least 12 months before enrolment. After an 8 week lead-in period to optimise diabetes management, patients were randomly assigned (1:1:1) using an interactive voice response system to dapagliflozin 5 mg or 10 mg once daily, given orally, or matched placebo. Randomisation was stratified by current use of continuous glucose monitoring, method of insulin administration, and baseline HbA1c. The primary efficacy outcome was the change from baseline in HbA1c after 24 weeks of treatment in the full analysis set, which consisted of all randomly assigned patients who received at least one dose of study drug. An additional 55 patients who were incorrectly and non-randomly allocated to only dapagliflozin treatment groups were included in the safety analysis set. This study was registered with ClinicalTrials.gov, number NCT02268214; data collection for the present analysis was completed on Jan 4, 2017, and a 28 week extension phase is ongoing. FINDINGS: Between Nov 11, 2014, and April 16, 2016, 833 patients were assigned to treatment groups and included in safety analyses (dapagliflozin 5 mg [n=277] vs dapagliflozin 10 mg [n=296] vs placebo [n=260]; 778 of these patients were randomly assigned and included in the full analysis set for efficacy analyses (259 vs 259 vs 260; difference due to randomisation error affecting 55 patients). Mean baseline HbA1c was 8·53% (70 mmol/mol; SD 0·67% [7·3 mmol/mol]). At week 24, both doses of dapagliflozin significantly reduced HbA1c compared with placebo (mean difference from baseline to week 24 for dapagliflozin 5 mg vs placebo was -0·42% [95% CI -0·56 to -0·28; p<0·0001] and for dapagliflozin 10 mg vs placebo was -0·45% [-0·58 to -0·31; p<0·0001]). Among patients in the dapagliflozin 5 mg (n=277), dapagliflozin 10 mg (n=296), and placebo (n=260) groups, the most common adverse events were nasopharyngitis (38 [14%] vs 36 [12%] vs 39 [15%]), urinary tract infection (19 [7%] vs 11 [4%] vs 13 [5%]), upper respiratory tract infection (15 [5%] vs 15 [5%] vs 11 [4%]), and headache (12 [4%] vs 17 [6%] vs 11 [4%]). Hypoglycaemia occurred in 220 (79%), 235 (79%), and 207 (80%) patients in the dapagliflozin 5 mg, dapagliflozin 10 mg, and placebo groups, respectively; severe hypoglycaemia occurred in 21 (8%), 19 (6%), and 19 (7%) patients, respectively. Adjudicated definite diabetic ketoacidosis occurred in four (1%) patients in the dapagliflozin 5 mg group, five (2%) in the dapagliflozin 10 mg group, and three (1%) in the placebo group. INTERPRETATION: Our results suggest that dapagliflozin is a promising adjunct treatment to insulin to improve glycaemic control in patients with inadequately controlled type 1 diabetes. FUNDING: AstraZeneca and Bristol-Myers Squibb.

Dapagliflozin in patients with type II diabetes mellitus, with and without elevated triglyceride and reduced high-density lipoprotein cholesterol levels.

BACKGROUND: Dapagliflozin is a selective sodium-glucose cotransporter 2 inhibitor that improves glycemic control in patients with type II diabetes mellitus (T2DM) by reducing renal glucose reabsorption. OBJECTIVE: The aim was to evaluate the lipid effects of dapagliflozin 10 mg or placebo in patients with T2DM with/without baseline elevated triglyceride and reduced high-density lipoprotein (HDL) cholesterol levels. METHODS: This was a post hoc analysis of 10 phase 3, placebo-controlled studies of dapagliflozin 10 mg (N = 2237) or placebo (N = 2164) administered for 24 weeks in patients with T2DM. Patients with elevated triglyceride (≥150 mg/dL [1.69 mmol/L]) and reduced HDL cholesterol levels (<40 mg/dL [1.04 mmol/L] in men; <50 mg/dL [1.29 mmol/L] in women) were included (group A). The reference group (group B) included patients who did not meet the defined lipid criteria. RESULTS: The effects of dapagliflozin on fasting lipid profiles were generally similar in the 2 lipid groups (ie, groups A and B) and, compared with placebo, were associated with minor increases in non-HDL cholesterol, low-density lipoprotein, and HDL cholesterol levels. The effects on triglyceride levels were inconsistent. The incidence of adverse events (AEs)/serious AEs, and AEs of genital infection, urinary tract infection, volume reduction, renal function, and hypoglycemia were similar in the 2 lipid groups. CONCLUSION: Patients with T2DM treated with dapagliflozin experienced minor changes in lipid levels; the changes were generally similar in the 2 lipid groups. The clinical significance of these changes in lipids is unclear, especially in view of the positive effects of dapagliflozin on other cardiovascular disease risk factors.

Differential Effects of Dapagliflozin on Cardiovascular Risk Factors at Varying Degrees of Renal Function.

BACKGROUND AND OBJECTIVE: Sodium glucose cotransporter 2 inhibition with dapagliflozin decreases hemoglobin A1c (HbA1c), body weight, BP, and albuminuria (urinary albumin-to-creatinine ratio). Dapagliflozin also modestly increases hematocrit, likely related to osmotic diuresis/natriuresis. Prior studies suggest that the HbA1c-lowering effects of dapagliflozin attenuate at lower eGFR. However, effects on other cardiovascular risk factors at different eGFR levels are incompletely understood. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This pooled analysis of 11 phase 3 clinical trials assessed changes in HbA1c, body weight, BP, hematocrit, and urinary albumin-to-creatinine ratio with placebo (n=2178) or dapagliflozin 10 mg (n=2226) over 24 weeks in patients with type 2 diabetes according to baseline eGFR (eGFR≥45 to <60 ml/min per 1.73 m2, eGFR≥60 to <90 ml/min per 1.73 m2, and eGFR≥90 ml/min per 1.73 m2). RESULTS: Compared with placebo, reductions in HbA1c with dapagliflozin were 0.6%, 0.5%, and 0.3%, respectively, for each consecutive lower eGFR subgroup (P value interaction <0.001). Effects of dapagliflozin on hematocrit, body weight, and BP were similar regardless of baseline eGFR, suggesting that effects potentially related to volume and natriuresis are eGFR independent. Moreover, among individuals with baseline urinary albumin-to-creatinine ratio ≥30 mg/g, placebo-adjusted reductions in urinary albumin-to-creatinine ratio were larger in the lowest eGFR subgroup (P value interaction <0.001). Adverse events occurred more frequently in the lowest eGFR subgroup; this was true for both dapagliflozin- and placebo-treated patients. CONCLUSIONS: The HbA1c-lowering effects of dapagliflozin decrease as renal function declines. However, dapagliflozin consistently decreases body weight, BP, and urinary albumin-to-creatinine ratio regardless of eGFR. These effects in conjunction with the finding of similar effects on hematocrit, a proxy for volume contraction, suggest that the effects of dapagliflozin are partly mediated via nonglucosuric-dependent mechanisms.

Efficacy and safety of dapagliflozin in patients with type 2 diabetes and concomitant heart failure.

AIM: We investigated the efficacy and safety of dapagliflozin, a sodium-glucose cotransporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) and heart failure (HF). METHODS: Data for patients randomized to dapagliflozin 10mg or placebo with a history of HF were pooled from five clinical trials. HbA1c, weight and systolic blood pressure (SBP; two studies) were examined up to 52weeks using longitudinal repeated-measures models. Composite cardiovascular outcomes, hospitalizations for HF (HHF), and adverse events (AEs) were also assessed. RESULTS: Patients (mean age 64years, T2DM duration ~14years, HbA1c 8.2%, ~50% with New York Heart Association Class ≥II) received dapagliflozin (N=171) or placebo (N=149). Dapagliflozin produced clinically meaningful placebo-adjusted reductions in HbA1c (-0.55%; 95% confidence interval [CI]: -0.80, -0.30), weight (-2.67kg; 95% CI: -3.88, -1.47), and SBP (-2.05mmHg; 95% CI: -5.68, 1.57) over 52weeks. HHF was rare, but numerically lower with dapagliflozin (n=1 [0.6%]) vs placebo (n=7 [4.7%]). Point estimates for hazard ratios of composite cardiovascular outcomes favored dapagliflozin vs placebo, although 95% CIs crossed unity. CONCLUSIONS: Dapagliflozin produced clinically meaningful reductions in HbA1c, weight, and SBP in patients with T2DM and HF, and was well tolerated.

Dapagliflozin in patients with type 1 diabetes: A post hoc analysis of the effect of insulin dose adjustments on 24-hour continuously monitored mean glucose and fasting ß-hydroxybutyrate levels in a phase IIa pilot study.

AIMS: To investigate the effects of total daily insulin dose (TDD) reductions on 24-hour continuously monitored mean glucose and fasting ß-hydroxybutyrate (a marker for diabetic ketosis/ketoacidosis [DKA]) levels, using patient-level data from a 14-day, pilot study of dapagliflozin in type 1 diabetes (T1DM). METHODS: A post hoc exploratory correlation analysis was performed to determine the relationship between change in TDD and (1) 24-hour mean glucose, assessed by continuous glucose monitoring, and (2) fasting ß-hydroxybutyrate, in 70 patients with T1DM receiving insulin and dapagliflozin (1, 2.5, 5 or 10 mg) or placebo. The pharmacodynamic effect of dapagliflozin was estimated as a virtual "insulin dose" using 24-hour urinary glucose excretion values and a recognized insulin-to-carbohydrate counting technique. RESULTS: Trends for correlations were observed between change in TDD and 24-hour glucose (day 7: r = -0.264, P = .056) and ß-hydroxybutyrate (day 7: r = -0.187, P = .133; day 14: r = -0.274, P = .047). The pharmacodynamic effect of dapagliflozin 5 or 10 mg was estimated as equivalent to ~20% of baseline TDD. Higher mean and maximum ß-hydroxybutyrate levels were observed on days 7 and 14 in patients with a TDD reduction >20% vs ≤20%. CONCLUSIONS: Over 14 days, decreasing the insulin dose diminished the glucose-lowering effect of dapagliflozin-insulin combination therapy and increased levels of ß-hydroxybutyrate. While insulin dose adjustments should always be individualized, these analyses suggest that, as a general rule, TDD reduction in dapagliflozin-treated patients with T1DM should not exceed 20%, to ensure glycaemic control does not deteriorate and to mitigate the potential for an increased risk of DKA.

Efficacy and Safety of Metreleptin in Patients with Partial Lipodystrophy: Lessons from an Expanded Access Program.

OBJECTIVE: Patients with lipodystrophy have severe metabolic abnormalities (insulin resistance, diabetes, and hypertriglyceridemia) that may increase morbidity and mortality. Metreleptin is approved by the United States Food and Drug Administration for treatment of generalized forms of lipodystrophy. We aimed to determine the efficacy and safety of metreleptin among patients with partial lipodystrophy using an expanded-access model. METHODS: Study FHA101 (ClinicalTrials.gov identifier: NCT00677313) was an open-label, expanded-access, long-term clinical effectiveness and safety study in 23 patients with partial lipodystrophy and diabetes and/or hypertriglyceridemia with no prespecified leptin level. Metreleptin was administered subcutaneously at 0.02 mg/kg twice daily (BID) at Week 1, followed by 0.04 mg/kg BID at Week 2. Dose adjustments thereafter were based on patient response (maximum dose of 0.08 mg/kg BID). One-year changes in glycated hemoglobin (HbA1c), fasting plasma glucose, triglycerides, alanine and aspartate aminotransferases, and treatment-emergent adverse events (TEAEs) were evaluated. RESULTS: HbA1c, fasting plasma glucose, and triglycerides were numerically decreased throughout 1 year, with mean (standard error) changes from baseline of -0.88 (0.62)%, -42.0 (22.4) mg/dL, and -119.8 (84.1) mg/dL, respectively, which were greater among patients with higher baseline abnormalities. Liver enzymes did not worsen, and the most frequently observed TEAEs (≥ 10% incidence) were mild to moderate and included nausea (39.1%), hypoglycemia (26.1%), and urinary tract infections (26.1%)-all reported previously. There were no reports of clinically significant immune-related adverse events or new safety signals. CONCLUSIONS: Our clinical observations document the large heterogeneity and disease burden of partial lipodystrophy syndromes and suggest that metreleptin treatment benefits may extend to patients with partial lipodystrophy. Additional studies are needed to confirm these preliminary findings.

Role of miR-155 in the pathogenesis of herpetic stromal keratitis.

Ocular infection with herpes simplex virus 1 can result in a chronic immunoinflammatory stromal keratitis (SK) lesion that is a significant cause of human blindness. A key to controlling SK lesion severity is to identify cellular and molecular events responsible for tissue damage and to manipulate them therapeutically. Potential targets for therapy are miRNAs, but these are minimally explored especially in responses to infection. Here, we demonstrated that Mir155 expression was up-regulated after ocular herpes simplex virus 1 infection, with the increased Mir155 expression occurring mainly in macrophages and CD4(+) T cells and to a lesser extent in neutrophils. In vivo studies indicated that Mir155 knockout mice were more resistant to herpes SK with marked suppression of T helper cells type 1 and 17 responses both in the ocular lesions and the lymphoid organs. The reduced SK lesion severity was reflected by increased phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase 1 and interferon-γ receptor α-chain levels in activated CD4(+) T cells in the lymph nodes. Finally, in vivo silencing of miR-155 by the provision of antagomir-155 nanoparticles to herpes simplex virus 1-infected mice led to diminished SK lesions and corneal vascularization. In conclusion, our results indicate that miR-155 contributes to the pathogenesis of SK and represents a promising target to control SK severity.

Bioequivalence of saxagliptin/metformin extended-release (XR) fixed-dose combination tablets and single-component saxagliptin and metformin XR tablets in healthy adult Chinese subjects.

BACKGROUND AND OBJECTIVES: As compared with individual tablets, saxagliptin/metformin extended-release (XR) fixed-dose combination (FDC) tablets offer the potential for increased patient compliance with the convenience of once daily dosing. The aim of the present study was to show that the FDC of saxagliptin and metformin XR is bioequivalent to co-administration of the individual components when given to Chinese subjects residing in China. METHODS: This was a randomized, open-label, single-dose, two-period, cross-over pharmacokinetic study in two cohorts of healthy adult Chinese male subjects (n = 32 in each cohort) under fed conditions. In cohort 1, the pharmacokinetic properties of a saxagliptin/metformin XR 5/500 mg FDC tablet were compared with those of co-administration of a 5 mg saxagliptin tablet and a 500 mg metformin XR tablet. In cohort 2, the pharmacokinetic properties of a saxagliptin/metformin XR 5/1,000 mg FDC tablet were compared with those of co-administration of a 5 mg saxagliptin tablet and 2 × 500 mg metformin XR tablets. The two cohorts were independent of each other with respect to treatment and results. The pharmacokinetic properties of the active metabolite of saxagliptin (5-hydroxy-saxagliptin), as well as the safety and tolerability of each treatment, were also evaluated. RESULTS: For both cohorts, saxagliptin and metformin in the FDCs were bioequivalent to the individual components, as the limits of the 90 % confidence intervals of the geometric least squares mean ratios were contained within the 80-125 % bioequivalence limits for the area under the plasma concentration-time curve parameters and within the 70-143 % bioequivalence limits for the maximum plasma concentration. Similar exposures of 5-hydroxy-saxagliptin were observed with the two treatment regimens within each cohort. Co-administration of saxagliptin and metformin XR was generally safe and well tolerated as the FDCs or as individual tablets. CONCLUSION: Saxagliptin/metformin XR 5/500 mg and saxagliptin/metformin XR 5/1,000 mg FDCs were bioequivalent to individual tablets of saxagliptin and metformin XR of the same strengths and were generally well tolerated. These results in healthy Chinese subjects are consistent with those of previous assessments of saxagliptin/metformin XR FDC in the saxagliptin clinical development programme.

Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma.

PURPOSE: A randomized, phase III, placebo-controlled, partially blinded clinical trial (REGAL [Recent in in Glioblastoma Alone and With Lomustine]) was conducted to determine the efficacy of cediranib, an oral pan-vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor, either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma. PATIENTS AND METHODS: Patients (N = 325) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 2:2:1 to receive (1) cediranib (30 mg) monotherapy; (2) cediranib (20 mg) plus lomustine (110 mg/m(2)); (3) lomustine (110 mg/m(2)) plus a placebo. The primary end point was progression-free survival based on blinded, independent radiographic assessment of postcontrast T1-weighted and noncontrast T2-weighted magnetic resonance imaging (MRI) brain scans. RESULTS: The primary end point of progression-free survival (PFS) was not significantly different for either cediranib alone (hazard ratio [HR] = 1.05; 95% CI, 0.74 to 1.50; two-sided P = .90) or cediranib in combination with lomustine (HR = 0.76; 95% CI, 0.53 to 1.08; two-sided P = .16) versus lomustine based on independent or local review of postcontrast T1-weighted MRI. CONCLUSION: This study did not meet its primary end point of PFS prolongation with cediranib either as monotherapy or in combination with lomustine versus lomustine in patients with recurrent glioblastoma, although cediranib showed evidence of clinical activity on some secondary end points including time to deterioration in neurologic status and corticosteroid-sparing effects.

Cediranib in combination with fulvestrant in hormone-sensitive metastatic breast cancer: a randomized Phase II study.

Hormone receptor-positive breast cancer is treated with estrogen inhibitors. Fulvestrant (FASLODEX™), an estrogen receptor (ER) antagonist with no known agonist effects, competitively binds, blocks and degrades the ER. Vascular endothelial growth factor (VEGF) may mediate resistance to ER antagonists. Cediranib is a highly potent VEGF signaling inhibitor with activity against all three VEGF receptors. This randomized Phase II study evaluated cediranib plus fulvestrant. Postmenopausal women with hormone-sensitive metastatic breast cancer were eligible. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), duration of response, clinical benefit rate (CBR), safety/tolerability and pharmacokinetics (PK). Patients received cediranib 45 mg/day (n=31) or placebo (n=31) both plus fulvestrant. Demographic/baseline characteristics were well balanced. Patients treated with cediranib had a numerical advantage in PFS (hazard ratio=0.867, P=0.669; median 223 vs. 112 days, respectively) and ORR (22 vs. 8 %, respectively) vs. placebo, although not statistically significant. CBR was 42 % in both arms. The most common adverse events (AEs) in the cediranib arm were diarrhea (68 %), fatigue (61 %) and hypertension (55 %). The incidence of grade ≥ 3 AEs (68 % vs. 32 %), serious AEs (48 % vs. 13 %), discontinuation AEs (39 % vs. 10 %), and cediranib dose reductions/interruptions (74 % vs. 32 %) were higher in the cediranib arm. There was no evidence of a clinically relevant effect of cediranib on fulvestrant PK. Cediranib plus fulvestrant may demonstrate clinical activity in this population, but cediranib 45 mg was not sufficiently well tolerated. Investigation of lower doses of cediranib plus hormonal/chemotherapy could be considered.