Anti-TGF-ß1 Antibody Therapy in Patients with Diabetic Nephropathy.

TGF-ß has been implicated as a major pathogenic factor in diabetic nephropathy. This randomized, double-blind, phase 2 study assessed whether modulating TGF-ß1 activity with a TGF-ß1-specific, humanized, neutralizing monoclonal antibody (TGF-ß1 mAb) is safe and more effective than placebo in slowing renal function loss in patients with diabetic nephropathy on chronic stable renin-angiotensin system inhibitor treatment. We randomized 416 patients aged ≥25 years with type 1 or type 2 diabetes, a serum creatinine (SCr) level of 1.3-3.3 mg/dl for women and 1.5-3.5 mg/dl for men (or eGFR of 20-60 ml/min per 1.73 m2), and a 24-hour urine protein-to-creatinine ratio ≥800 mg/g to TGF-ß1 mAb (2-, 10-, or 50-mg monthly subcutaneous dosing for 12 months) or placebo. We assessed a change in SCr from baseline to 12 months as the primary efficacy variable. Although the Data Monitoring Committee did not identify safety issues, we terminated the trial 4 months early for futility on the basis of their recommendation. The placebo group had a mean±SD change in SCr from baseline to end of treatment of 0.33±0.67 mg/dl. Least squares mean percentage change in SCr from baseline to end of treatment did not differ between placebo (14%; 95% confidence interval [95% CI], 9.7% to 18.2%) and TGF-ß1 mAb treatments (20% [95% CI, 15.3% to 24.3%], 19% [95% CI, 14.2% to 23.0%], and 19% [95% CI, 14.0% to 23.3%] for 2-, 10-, and 50-mg doses, respectively). Thus, TGF-ß1 mAb added to renin-angiotensin system inhibitors did not slow progression of diabetic nephropathy.

Pharmacokinetics and safety of single doses of tabalumab in subjects with rheumatoid arthritis or systemic lupus erythematosus.

AIMS: Two phase 1 studies evaluated the pharmacokinetics (PK), safety and biological activity of tabalumab, a human monoclonal antibody against B-cell activating factor (BAFF), administered intravenously (i.v.) or subcutaneously (s.c.) in subjects with rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE). METHODS: In study A, subjects with RA (n = 23) or SLE (n = 6) received a single i.v. dose of tabalumab (RA 0.01, 0.04, 0.125, 0.5, 2.0, and 8.0 mg kg(-1) and SLE 0.125 or 2.0 mg kg(-1) ) or placebo. In study B, subjects with RA received a single tabalumab dose i.v. (10 mg) (n = 12) or s.c. (20 mg) (n = 12). Serum tabalumab and CD20+ B cells were evaluated and safety was assessed throughout both studies. RESULTS: Tabalumab PK were non-linear across the 0.01 to 8.0 mg kg(-1) dose range. Clearance (CL) decreased from 2.9 to 0.1 l day(-1) and terminal half-life (t1/2 ) increased from about 1.6 to 25 days. Subjects with RA or SLE had similar PK. After s.c. dosing, tabalumab time to maximal concentration (tmax ) was 5.5 days. Absolute bioavailability (F) was approximately 62%. Following tabalumab dosing, CD20+ B cells transiently increased from baseline followed by a progressive decrease below baseline. CONCLUSION: A single tabalumab dose administered i.v. or s.c. was well tolerated and had non-linear CL over the dose range investigated in subjects with RA and SLE. The non-linearity likely reflects target-mediated CL due to binding to BAFF. Tabalumab showed biological activity based on changes in peripheral CD20+ lymphocyte numbers in both subjects with RA and SLE.

A prospective study of multiple protein biomarkers to predict progression in diabetic chronic kidney disease.

BACKGROUND: Diabetic nephropathy imposes a substantial cardiovascular and renal burden contributing to both morbidity and excess mortality. Progression of chronic kidney disease (CKD) in diabetes mellitus is variable, and few biomarkers are available to predict progression accurately. Identification of novel predictive biomarkers may inform clinical care and assist in the design of clinical trials. We hypothesized that urinary and plasma protein biomarkers predict CKD progression independently of the known clinical markers such as albuminuria and estimated glomerular filtration rate (eGFR) in diabetic nephropathy. METHODS: We studied 67 US veterans with CKD due to type 2 diabetes mellitus and 20 age-matched controls (no CKD, hypertension or cardiovascular disease). After clinical evaluation and the collection of blood and urine specimens for 24 biomarkers, we followed subjects prospectively for the next 2-6 years. CKD progression was defined in three ways: (i) clinically by examining eGFR versus time plots for each individual (slope progression), (ii) progression to end-stage renal disease (ESRD) and (iii) a composite outcome of ESRD or death. RESULTS: Among 17 urinary and 7 plasma biomarkers evaluated, the relationship of the biomarkers with outcome was as follows: (i) for progression identified by eGFR plots, urinary C-terminal fibroblast growth factor (FGF)-23 emerged to have the strongest primary association (adjusted odds ratio [aOR] 2.08, P = 0.008); (ii) for ESRD, plasma vascular endothelial growth factor (VEGF) had an association (aOR: 1.44, P = 0.027) and (iii) for the composite outcome of death and ESRD, plasma C-terminal FGF-23 also had a robust direct association (aOR: 3.07, P = 0.008). CONCLUSION: The relationship of biomarkers with future progression of CKD is complex and depends in part on how CKD progression is defined. Biomarkers in the FGF-23 and VEGF-A pathways predicted patient progression independently of albuminuria levels in this patient cohort. Additional studies in other cohorts will help further validate this pilot study.

Estimating the distribution of a novel clinical biomarker (FGF-23) in the US population using findings from a regional research registry.

Evidence of involvement of novel biomarkers in disease pathogenesis from research cohorts often precedes an understanding of their distributions in broader populations. This study aimed to estimate the distribution of fibroblast growth factor 23 (FGF-23), an endocrine hormone that helps to regulate serum phosphate levels, in the overall US population and in important subgroups. We used a predictive model generated using data from the Framingham Health Study to estimate FGF-23 values for adults in the US National Health and Nutrition Examination Survey and the size of patient subgroups with levels of FGF-23 above selected thresholds. To assess the face validity of our FGF-23 estimates, we examined the relationship between estimated FGF-23 and cardiovascular and all-cause mortality within NHANES using Kaplan-Meier estimates and Cox proportional-hazards regression models and compared it to that observed in Framingham. Estimated FGF-23 values from NHANES were lower (median [interquartile range] 47.4 [35.8, 64.0] vs. 67.0 [54.0, 85.0] RU/mL) than the observed FGF-23 values from the Framingham cohort. Age- and sex-adjusted 10-year all-cause mortality was significantly higher (hazard ratio 2.43 [95% confidence interval: 1.42, 4.16]) for subjects with estimated FGF-23 levels in the highest versus lowest quartile. Estimating the distribution of biomarker values in the general population by applying predictive equations from smaller research cohorts is feasible and can inform drug research decision making.

LY3045697: Results from two randomized clinical trials of a novel inhibitor of aldosterone synthase.

INTRODUCTION: LY3045697 is a potent and selective aldosterone synthase (CYP11B2) inhibitor that was developed as a safer alternative to mineralocorticoid receptor antagonists. Effects of LY3045697 on aldosterone and cortisol synthesis, as well as potassium ion homeostasis, were evaluated in two clinical studies in healthy subjects. MATERIALS AND METHODS: Two incomplete, placebo-controlled crossover-design clinical studies examined safety, pharmacodynamics, and pharmacokinetics under single and repeated dose conditions in healthy subjects. Pharmacodynamics was assessed following oral potassium challenge and intravenous adrenocorticotropic hormone procedures with spironolactone 25 mg/d as an active comparator. RESULTS: A total of 51 subjects participated in the two studies, which included 38 males and 13 females (of non-childbearing potential), from 18-65 years old. LY3045697 caused rapid dose and concentration-dependent unstimulated plasma aldosterone concentration reduction seen as early as 4 h after the first dose at dose levels as low as 1 mg, and reaching near complete suppression at high doses. The potency (IC50) decreased significantly upon multiple dosing. After eight days of dosing, post-adrenocorticotropic hormone challenge plasma aldosterone concentration increase was dose-dependently blunted by LY3045697 with high potency with a dose as low as 0.1 mg resulting in substantial effect, and with an overall IC50 of 0.38 ng/ml. Minor reductions in cortisol were observed only at the top dose of 300 mg. LY3045697 is generally safe and tolerated, and exhibits linear pharmacokinetics. CONCLUSIONS: LY3045697 is a potent and highly selective aldosterone synthase inhibitor with selectivity for CYP11B2, offering a substantial potential advantage over previous aldosterone synthase inhibitors evaluated in the clinic.

Effects of chronic renal failure on the pharmacokinetics of ruboxistaurin and its active metabolite 338522.

BACKGROUND: Ruboxistaurin, a specific inhibitor of the beta(1) and beta(2) isoforms of protein kinase C, is currently in clinical development for the treatment of several diabetic microvascular complications. The major metabolite, N-desmethyl ruboxistaurin (metabolite 338522), is equipotent in its inhibitory activity. The elimination of ruboxistaurin and its metabolites is primarily through bile and the faecal route, with urinary excretion constituting only a minor route. OBJECTIVE: To assess the effects of chronic renal insufficiency on the pharmacokinetics of ruboxistaurin and metabolite 338522. METHODS: Six healthy subjects (creatinine clearance >80 mL/min/1.73 m(2)) and six end-stage renal disease (ESRD) subjects requiring long-term haemodialysis were studied. All subjects received a single oral dose of ruboxistaurin 32 mg followed by serial blood sampling up to 72 hours. ESRD subjects underwent haemodialysis approximately 58 hours after dosing, with blood samples obtained immediately before and after dialysis. RESULTS: No differences were observed in the pharmacokinetic parameters (area under the plasma concentration-time curve from time zero to infinity [AUC(infinity)], maximum plasma concentration [C(max)] and elimination half-life [t(1/2)]) of ruboxistaurin and metabolite 338522 between healthy and ESRD subjects Plasma concentrations of ruboxistaurin were below the lower limit of quantification by the time of haemodialysis. The predicted post-dialysis plasma concentrations of metabolite 338522 were not statistically different from the observed values (p=0.163). Ruboxistaurin was well tolerated in both groups of subjects. CONCLUSION: These results indicate that the kidney is not an important route of metabolism or excretion for ruboxistaurin and metabolite 338522. Based on the pharmacokinetic and tolerability findings, no formal dosage adjustment of ruboxistaurin should be required for patients with any degree of renal impairment who are undergoing haemodialysis.

Teriparatide has no effect on the calcium-mediated pharmacodynamics of digoxin.

BACKGROUND: Teriparatide (recombinant human parathyroid hormone [1-34]) stimulates bone formation and causes small transient increases in serum calcium concentration. We assessed whether teriparatide causes a change in digoxin pharmacodynamic effects by measuring systolic time intervals and heart rate. METHODS: Measurements were made by echocardiographic Doppler that examined 3 systolic time intervals, as follows: QS(2) (time from Q wave on electrocardiogram to the closure of the aortic valve), left ventricular ejection time, and pre-ejection period, all corrected for changes in heart rate. Fifteen healthy subjects (2 men and 13 women) were administered a single subcutaneous teriparatide dose (20 microg) on day 1 and then equilibrated on a daily oral dose of digoxin for 15 days. Subcutaneous placebo and teriparatide, 20 microg, were given in a randomized crossover design with the 14th (day 15) and 15th (day 16) digoxin doses. Serial systolic time interval and heart rate measurements were obtained on days 1, 15, and 16. RESULTS: After subjects were dosed to steady state with digoxin, there were statistically significant reductions in QS(2) corrected for heart rate (QS(2)c) of 23 to 25 ms and heart rate of 4 to 6 beats/min. However, there was no difference between treatment with digoxin plus placebo versus digoxin plus teriparatide. The study was powered to find a difference in QS(2)c as small as 6 ms (alpha =.05, beta =.2). CONCLUSION: Teriparatide, 20 microg subcutaneously, does not alter the cardiac effect of digoxin.

Pharmacokinetics of ruboxistaurin are significantly altered by rifampicin-mediated CYP3A4 induction.

AIMS: The aim of this study was to evaluate the effect of rifampicin co-administration on the pharmacokinetics of ruboxistaurin and its active metabolite, N-desmethyl ruboxistaurin and, in addition, to compare the changes in pharmacokinetics of ruboxistaurin and N-desmethyl ruboxistaurin with the urinary 6beta-hydroxycortisol : cortisol ratio. Ruboxistaurin is a specific protein-kinase-C beta inhibitor in clinical development for the treatment of diabetic microvascular complications. METHODS: This was a two-period, one-sequence study. Sixteen healthy male subjects completed both study periods. In period one, a single 64 mg oral dose of ruboxistaurin was administered. In period two, 600 mg rifampicin was administered daily for 9 days, during which another single 64 mg ruboxistaurin dose was administered on day 7. Blood samples were collected and assayed for ruboxistaurin and N-desmethyl ruboxistaurin. CYP3A4 induction was assessed by ratios of urinary 6beta-hydroxycortisol : cortisol (6beta-OHC : C) obtained via 24 h and morning-spot sampling techniques. Results Following repeated doses of rifampicin, both the mean C(max) and AUC(0,infinity) of ruboxistaurin were significantly reduced by approximately 95% (P < or = 0.001). For the metabolite, the mean C(max) decreased by 68% (P < or = 0.001), and AUC(0,infinity) decreased by 77% (P < or = 0.001). The t(max) values did not appear affected. The 6beta-OHC : C ratios from both 24 h and morning spot methods increased significantly, consistent with CYP3A4 induction. CONCLUSIONS: The effect of rifampicin co-administration on the exposure of ruboxistaurin is consistent with ruboxistaurin being a substrate of CYP3A4. Therefore, co-administration with known CYP3A4 inducing agents (rifampicin, carbamazepine, phenobarbital, etc.) may decrease the concentrations of ruboxistaurin and N-desmethyl-ruboxistaurin. In this study, 6beta OHC : C ratios substantially underestimated the impact of rifampicin on ruboxistaurin.