Anne Gill

Obesity, diabetes, and neoplasia in yellow A(vy)/- mice: ectopic expression of the agouti gene.

The viable yellow Avy mutation results in a mottled yellow mouse that is obese, slightly larger than its nonyellow sibs, and more susceptible to tumor formation in those tissues sensitized by the strain genome. The mutation exhibits variable expressivity resulting in a continuum of coat color phenotypes, from clear yellow to pseudoagouti. The mouse agouti protein is a paracrine signaling molecule that induces hair follicle melanocytes to switch from the synthesis of black pigment to yellow pigment. Molecular cloning studies indicate that the obesity and growth effects of the Avy mutation result from ectopic expression of the normal agouti gene product. This review seeks to summarize the current state of knowledge regarding the obesity, stimulation of somatic growth, and enhancement of tumor formation caused by the Avy mutation, and to interpret these pleiotropic effects in terms of the normal function of the agouti protein.—Yen, T. T., Gill, A. M., Frigeri, L. G., Barsh, G. S., and Wolff, G. L. Obesity, diabetes, and neoplasia in yellow Avy/‐ mice: ectopic expression of the agouti gene. FASEB J. 8: 479‐488; 1994.

Effect of exenatide on heart rate and blood pressure in subjects with type 2 diabetes mellitus: a double-blind, placebo-controlled, randomized pilot study

BackgroundCardiovascular effects of glucose-lowering agents are of increasing interest. Our aim was to assess the effects of the glucagon-like peptide-1 receptor agonist exenatide on heart rate (HR) and blood pressure (BP) in subjects with type 2 diabetes mellitus (T2DM).MethodsIn this double-blind, placebo-controlled trial, subjects with T2DM on metformin and/or a thiazolidinedione were randomized to receive exenatide (5 μg for 4 weeks followed by 10 μg) or placebo BID for 12 weeks. Heart rate and BP were assessed with 24-hour ambulatory BP monitoring. The primary measure was change from baseline in mean 24-hour HR.ResultsFifty-four subjects (28 exenatide, 26 placebo) were randomized and comprised the intent-to-treat population. Baseline values (exenatide and placebo) were (mean ± SE) 74.4 ± 2.1 and 74.5 ± 1.9 beats/minute for HR, 126.4 ± 3.2 and 119.9 ± 2.8 mm Hg for systolic BP (SBP), and 75.2 ± 2.1 and 70.5 ± 2.0 mm Hg for diastolic BP (DBP). At 12 weeks, no significant change from baseline in 24-hour HR was observed with exenatide or placebo (LS mean ± SE, 2.1 ± 1.4 versus -0.7 ± 1.4 beats/minute, respectively; between treatments, p = 0.16). Exenatide therapy was associated with trends toward lower 24-hour, daytime, and nighttime SBP; changes in DBP were similar between groups. No changes in daytime or nighttime rate pressure product were observed. With exenatide, body weight decreased from baseline by -1.8 ± 0.4 kg (p < 0.0001; treatment difference -1.5 ± 0.6 kg, p < 0.05). The most frequently reported adverse event with exenatide was mild to moderate nausea.ConclusionsExenatide demonstrated no clinically meaningful effects on HR over 12 weeks of treatment in subjects with T2DM. The observed trends toward lower SBP with exenatide warrant future investigation.Trial registrationNCT00516074

Effects of ciglitazone on endogenous plasma islet amyloid polypeptide and insulin sensitivity in obese-diabetic viable yellow mice

The role of islet amyloid polypeptide, also known as amylin, in insulin resistance and in the etiology of diabetes has been a subject of debate. Increased plasma amylin levels have been observed in both obese and type II diabetic patients. However, data on endogenous amylin levels with relation to pharmacological interventions have not been reported. In this study, chronic treatment of obese-diabetic viable yellow mice with ciglitazone was shown to significantly alter various parameters. Blood glucose and plasma insulin, triglyceride, and amylin levels were reduced and glucose tolerance in the presence of exogenous insulin was improved. Insulin/amylin ratios which were found to be significantly elevated in diabetic mice as compared to normal controls, were decreased after ciglitazone treatment. However, observed decreases in both amylin and insulin concentrations due to ciglitazone treatment and their subsequent increases upon withdrawal of treatment were correlated, suggesting cosecretion.

Pancreatic Islet Cells in Preobese Yellow Avy/- Mice: Relation to Adult Hyperinsulinemia and Obesity:

Abstract Plasma insulin levels in yellow Avy /- mice begin to increase before the animals are overtly obese. Are the elevated insulin levels in yellow mice primary or secondary to the subsequent obesity? Elevated blood insulin levels in young preobese mice, due to synthesis and release of insulin by increased number of β cells, would stimulate lipogenesis, resulting in excess lipid deposition and subsequent peripheral insulin resistance. Examination of this possibility was the objective of this study. The β, α, and δ cells in the pancreata of 7-, 14-, and 21-day-old male yellow Avy/A and agouti A/a (BALB/c x VY)F1 hybrid mice were counted with immunohistochemical/morphometric techniques. The insulin and glucagon concentrations in pancreata from male and female mice of the same ages and genotypes were also assayed. In the 21-day-old male mice, the mean number of β cells/pancreas was significantly greater in the yellow mice than in the agouti mice; however, insulin content and body weight were the same. This suggests that increased β cell proliferation in yellow mice precedes any detectable genotype-specific increase in pancreatic insulin content or body weight.

Dexamethasone-Induced Hyperglycemia in Obese Avy/a (Viable Yellow) Female Mice Entails Preferential Induction of a Hepatic Estrogen Sulfotransferase

Sex steroid sulfotransferases (ST) sulfurylate and thus inactivate estrogens or androgens, producing an androgenized or estrogenized state in the liver. The expression of diabetes in a number of animal models is sexually dimorphic and has been associated with steroidal states. Although the viable yellow (Avy) mutation produces an insulin-resistant obesity syndrome in mice of both sexes, only males develop chronic hyperglycemia. Hyperglycemia was rapidly induced in Avy/a females by dexamethasone (dex). This treatment completely suppressed both endogenous plasma corticosterone and hepatic corticosterone-binding globulin (CBG) mRNA within 24 h. Hyperglycemia in dex-implanted Avy/a females was accompanied by aberrant shifts in hepatic androgen/estrogen balance. This was effected by induction of estrogen sulfotransferase (EST) mRNA together with a > 10-fold increase in enzymatic activity. Similar dex-induced increases in androgen ST or phenol ST were not observed. Prior implantation of estrogen prevented development of hyperglycemia. The time-dependent spontaneous reversal of dex-induced hyperglycemia correlated with re-expression of CBG mRNA transcripts and reduced levels of EST transcripts and enzyme activity. Although dex-induced hyperglycemia was limited to Avy/a females, dex elicited hyperinsulinemia in lean α/α control mice of both sexes and exacerbated constitutive hyperinsulinemia in Avy/a males and females. In summary, dex-induced hyperglycemia in Avy/a females was associated with increased catabolism of hepatic estrogens mediated by induction of EST.

Efficacy and safety of tabalumab, an anti-B-cell-activating factor monoclonal antibody, in patients with rheumatoid arthritis who had an inadequate response to methotrexate therapy: results from a phase III multicentre, randomised, double-blind study

Objectives Randomised, double-blind, placebo-controlled study to evaluate efficacy and safety of tabalumab in patients with rheumatoid arthritis (RA) with inadequate responses to methotrexate (MTX-IR). Methods 1041 patients with moderate–severe RA despite ongoing MTX enrolled in a 52-week study evaluating subcutaneous tabalumab 120 mg every four weeks (120/Q4W) or 90 mg every two weeks (90/Q2W) versus placebo. Primary endpoints were American College of Rheumatology 20% (ACR20) response rate and Health Assessment Questionnaire-Disability Index change from baseline at 24 weeks and modified Total Sharp Score (mTSS) change at 52 weeks. Results There were no significant differences in ACR20 responses at week 24 or mTSS change from baseline at week 52 among treatment groups. Declines were seen in CD20+ B cells and immunoglobulin levels in tabalumab groups, but not placebo: B cells (−15.0%, −18.8%, 5.3%, in the 120/Q4W, 90/Q2W, and placebo groups, respectively); IgM (−16.3%, −19.4%, −0.1%), IgA (−11.4%, −4.7%, 1.2%) and IgG (−8.6%, −7.8%, 0.1%). Discontinuations due to adverse events were similar between groups. Numerically more serious infections were reported in tabalumab groups (1.7%, 0.6%, 0.3%); numerically more injection-site reactions were reported in the 90/Q2W group (2.3%, 4.3%, 2.3%). Conclusions Neither clinical efficacy nor significant safety signals were observed with tabalumab despite evidence of biological activity. This study was terminated early due to insufficient efficacy. Trial registration number NCT01198002.

Phase 3, open-label, randomized study of the pharmacokinetics, efficacy and safety of ixekizumab following subcutaneous administration using a prefilled syringe or an autoinjector in patients with moderate-to-severe plaque psoriasis (UNCOVER-A).

The efficacy of ixekizumab, an anti‐interleukin‐17A (anti‐IL‐17A) monoclonal IgG4 antibody, was demonstrated in moderate‐to‐severe psoriasis patients when administered via prefilled syringe (PFS).

Efficacy and safety of tabalumab, an anti-BAFF monoclonal antibody, in patients with moderate-to-severe rheumatoid arthritis and inadequate response to TNF inhibitors: results of a randomised, double-blind, placebo-controlled, phase 3 study.

Background Tabalumab is a human monoclonal antibody that neutralises B-cell activating factor. Objectives To evaluate tabalumab efficacy and safety in patients with rheumatoid arthritis (RA). Methods This phase 3, randomised, double-blind, placebo-controlled study evaluated 456 patients with active RA after 24-week treatment with subcutaneous tabalumab (120 mg every 4 weeks (120/Q4W) or 90 mg every 2 weeks (90/Q2W)) versus placebo, with loading doses (240 or 180 mg) at week 0. Patients were allowed background disease-modifying antirheumatic drugs and previously discontinued ≥1 tumour necrosis factor α inhibitors for lack of efficacy/intolerance. Primary end point was American College of Rheumatology 20% (ACR20) response at 24 weeks. This study was terminated early due to futility. Results Most patients had moderate-to-high baseline disease activity. There was no significant difference in week 24 ACR20 responses between 120/Q4W, 90/Q2W, and placebo (17.6%, 24.3%, 20%) per non-responder imputation analysis. Mean percent changes in CD20+ B-cell count (−10.8%, −9.6%, +10.9%) demonstrated expected pharmacodynamic effects. Treatment-emergent adverse events (AEs) were similar (59.5%, 51.7%, 52.6%), as were AE discontinuations (2.6%, 2.7%, 2.6%), serious AEs (4.6%, 4.1%, 3.9%), serious infectious events (1.3%, 0, 0) and events of interest: infections (23.5%, 25.9%, 24%), injection site reactions (13.1%, 25.8%, 11%) and allergy/hypersensitivity (3.9%, 4.1%, 3.9%) reports. Incidence of treatment-emergent antidrug antibodies was similar to placebo (3.9%, 4.8%, 3.9%). No deaths or new/unexpected safety findings were reported. Conclusions Tabalumab did not demonstrate clinical efficacy in patients with RA in this phase 3 study, despite evidence of biological activity. There were no notable differences in safety parameters between tabalumab treatment groups and placebo. Trial registration number: NCT01202773.

Usability of a novel disposable autoinjector device for ixekizumab: results from a qualitative study and an open-label clinical trial, including patient-reported experience

Background Most biologic therapies for psoriasis are delivered via subcutaneous injection. Ixekizumab, an anti-interleukin 17A monoclonal antibody approved for patients with moderate-to-severe plaque psoriasis, is delivered subcutaneously via prefilled syringe or autoinjector. Here we report the results of an ixekizumab autoinjector usability study as well as the patient-reported experience with the autoinjector in a clinical trial. Methods The usability study enrolled 49 subjects (patients with a range of autoimmune conditions or their caregivers). Subjects were randomized to a trained or untrained group and were evaluated for their ability to perform an injection successfully when provided the device and the instructions for use. In the clinical trial, 102 subjects (patients with psoriasis or their caregivers) used the autoinjector to deliver injections of ixekizumab (80 mg every 2 weeks after a starting dose of 160 mg). At weeks 0, 4, and 8, subjects completed the subcutaneous administration assessment questionnaire, which assesses the ease of use and confidence with using an injection device. Results In the usability study, all subjects in the untrained arm performed successful injections, while two subjects in the trained arm had an injection failure. These incidences were not consistent with any pattern of issues with the device or the instructions for use. In the clinical trial, there were two injection failures of 674 total self-injections performed over 12 weeks. At the first use of the device, 95% of subjects either agreed or strongly agreed that the device was “overall easy to use”, and they felt “confident the dose was complete” according to the subcutaneous administration assessment questionnaire. Conclusion The ixekizumab autoinjector was used successfully by patients and caregivers with or without training. Subjects using the autoinjector in a clinical trial felt it was easy to use and felt confident while using it.

Efficacy and Safety of Tabalumab, an Anti-B-Cell-Activating Factor Monoclonal Antibody, in a Heterogeneous Rheumatoid Arthritis Population: Results From a Randomized, Placebo-Controlled, Phase 3 Trial (FLEX-O).

ObjectivesThe efficacy and safety of 2 different dosing regimens of tabalumab, a monoclonal antibody that neutralizes membrane-bound and soluble B-cell–activating factor (BAFF), were evaluated in patients with rheumatoid arthritis. MethodsIn this phase 3, multicenter, randomized study, 1004 patients (intention-to-treat population) received subcutaneous 120 mg tabalumab every 4 weeks (120/Q4W), 90 mg tabalumab every 2 weeks (90/Q2W), or placebo over 24 weeks. At baseline, a loading dose double the planned dose (ie, 240 mg, 180 mg, or placebo) was administered. Efficacy analyses were based on a prespecified subset of patients with 5 or more of 68 tender and 5 or more of 66 swollen joints at baseline (efficacy population, n = 849). The primary efficacy end point was ACR20 (20% improvement in American College of Rheumatology criteria) response at week 24. ResultsAt week 24, there were no differences in ACR20 response rates (120/Q4W = 34.4%, 90/Q2W = 33.5%, placebo = 31.5%) or any other measures of efficacy across the treatment groups. Discontinuations due to adverse events (AE) were 3.4%, 2.7%, and 4.0%; incidence of treatment-emergent AEs were 64.1%, 58.2%, and 58.8%, with 23.2%, 25.9%, and 22.0% treatment-emergent infections; and incidence rates of serious AEs were 3.7%, 2.2%, and 2.8% with 1.1%, 0.3%, and 0.7% serious infections in the 120/Q4W, 90/Q2W, and placebo groups, respectively. Three deaths were reported (120/Q4W, n = 2; 90/Q2W, n = 1). Each tabalumab group had significant decreases versus placebo in CD3-CD20+ B cells (P ⩽ 0.05) and in serum immunoglobulins (P ⩽ 0.001). ConclusionsAlthough tabalumab administration resulted in biologic activity, as demonstrated by changes in B cells and immunoglobulins, targeting BAFF-dependent pathways alone is not sufficient to significantly reduce rheumatoid arthritis disease activity.