Safety and pharmacodynamic dose response of short-term prednisone in healthy adult subjects: a dose ranging, randomized, placebo-controlled, crossover study.

BACKGROUND: Glucocorticoids (GCs), such as prednisone, are the standard of care for several inflammatory and immunologically mediated diseases, but their chronic systemic administration is severely limited by serious adverse effects that are both dose and time dependent. Short-term treatment (7-14 days) with oral prednisone is used for many acute inflammatory and allergic conditions. This study was conducted to characterize the safety and pharmacodynamic (PD) dose-response of a 7-day course of oral prednisone on biomarkers of GC receptor agonism. METHODS: In this randomized, single-blind, placebo-controlled, crossover study (A9001309), 37 healthy subjects received placebo or a prednisone dose from 2.5-60 mg daily over 7 days in each of three treatment periods. White blood cell counts and plasma samples for measuring cortisol, osteocalcin and procollagen type 1 N-propeptide (P1NP) were obtained at 2, 4, 8, and 12 h post-dose on Day 1, immediately prior to dosing on Days 1, 2, and 4, and at nominal dosing time on Days 0 and 8. Urine samples for urinary N-terminal cross-linked telopeptide of type 1 collagen (uNTX) were collected on Days 0, 1, 2, 4, and 8. Serum samples for adiponectin were obtained prior to dosing on days 0, 1, 4 and 8. RESULTS: Daily doses of prednisone up to 60 mg resulted in dose- and time-dependent decreases in plasma osteocalcin, plasma P1NP, serum cortisol, and absolute blood eosinophil counts. Absolute blood neutrophil counts increased, while blood lymphocyte counts rebounded to an increased level following an initial rapid decrease after dosing. An increase was observed for uNTX and adiponectin. The incidence of adverse effects with prednisone was not dose related, and nervous system disorders, mainly headache, were the most frequently reported adverse effects. CONCLUSIONS: This characterization provides important and relevant information on safety and PD responses of short-term prednisone dosing over the commonly-used clinical dose range, and also provides a reference for early clinical development of dissociated agents targeting a differentiated PD profile. TRIAL REGISTRATION NUMBER: NCT02767089 (retrospectively registered: 21 April 2016).

A Phase 1 Dose-Escalation Study of ASP2409, a Selective T-Cell Costimulation Inhibitor, in Stable Rheumatoid Arthritis Patients on Methotrexate Therapy.

ASP2409 represents a new class of CTLA4-Ig molecules with higher binding avidity and selectivity to CD86. This first-in-human study was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of ASP2409 in stable rheumatoid arthritis patients on methotrexate therapy with a randomized, double-blind, placebo-controlled dose-escalation study design. Patients were enrolled and randomized in each of 8 dose-escalation cohorts ranging from 0.001 to 3.0 mg/kg to receive either ASP2409 or placebo in a sequential manner. Escalation to higher dose levels occurred in the absence of dose-limiting toxicity. A total of 57 patients completed the study. ASP2409 showed nonlinear PK over the dose range of 0.01 to 3.0 mg/kg following a single intravenous administration, indicating target-mediated drug disposition. Area under the concentration-time curve (AUC) and maximum concentration (Cmax ) increased at a greater than dose-proportional rate. The half-life of ASP2409 increased dose dependently and ranged from 1.57 to 6.68 days. ASP2409 showed a dose-dependent increase in the extent and duration of CD86 receptor occupancy. There were no clinically relevant safety issues up to a single dose of 3.0 mg/kg. No maximum tolerated dose was reached. The incidence and duration of antidrug antibodies did not correlate with adverse events. ClinicalTrials.gov identifier: NCT02171143.

Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of ASP2408, a Potent Selective T-Cell Costimulation Modulator After Single and Multiple Ascending Doses in Healthy Volunteers and RA Patients.

ASP2408 is a next-generation anti-cytotoxic T lymphocyte antigen-4 fusion protein engineered for improved CD86 binding affinity as a treatment for rheumatoid arthritis (RA). In 72 healthy subjects (n = 6/treatment), ASP2408 was administered as single ascending doses intravenously at 0.003 to 10.0 mg/kg or subcutaneously at 0.3 to 3.0 mg/kg. It showed decreased clearance and prolonged half-life with increasing doses, consistent with target-mediated disposition. The apparent bioavailability was 36.3%-56.7% across single subcutaneous doses. Sixteen RA patients (n = 8/treatment) on stable methotrexate received 3 × 3.0 mg/kg subcutaneously every 4 weeks or every 2 weeks. Similar to single-dose treatment, ASP2408 concentrations peaked 2 to 3 days postdose, with a median t1/2 of approximately 8 days. Using CD86 receptor occupancy (RO) as a mechanistic biomarker, ASP2408 demonstrated dose-dependent binding to its target. ASP2408 3.0 mg/kg subcutaneously every 4 weeks and every 2 weeks led to a mean %CD86 RO ≥ 74.7% and ≥ 81.5%, respectively, within each dosing interval. ASP2408 was well tolerated across studies with no evidence of dose-limiting toxicity or clinically significant changes in clinical laboratory test results, vital signs, or 12-lead electrocardiograms. ASP2408 elicited antidrug antibodies in the majority of patients, but with no clinical sequelae.

Safety profile and tolerability of up to 1 year of pregabalin treatment in 3 open-label extension studies in patients with fibromyalgia.

BACKGROUND: Pain relief and an acceptable safety profile have been reported in randomized controlled trials (RCTs) of pregabalin in the treatment of fibromyalgia (FM) for up to 14 weeks. OBJECTIVE: To evaluate the safety profile and tolerability of pregabalin (75-300 mg BID) treatment for up to 1 year in patients with FM. METHODS: Twelve-week data were pooled from 3 open-label extension studies of pivotal RCTs. Study 1 was a 1-year extension of a 13-week RCT, and studies 2 and 3 were 12-week extensions of 14-week RCTs. The 1-year data were separately evaluated. The open-label data are summarized using descriptive statistics. RESULTS: Overall, 1206 patients (92.4% female) with a mean (SD) age of 48.8 (10.7) years received open-label extended pregabalin treatment. A total of 119 of 1206 patients (9.9%) permanently discontinued study participation due to treatment-emergent adverse events (all causality) at 12 weeks (pooled data) and 53 of 429 (12.4%) within 1 year. Consistent with previous RCTs, the most commonly reported treatment-emergent adverse events with open-label pregabalin treatment were dizziness, somnolence, headache, peripheral edema, and increased weight. The highest incidence rates in the pooled 12-week data were for dizziness (214 of 1206; 17.7%) and somnolence (96 of 1206; 8.0%). In ratings of severity (mild, moderate, severe), most were reported as mild to moderate. The mean (SD) change in patient-reported visual analog scale pain scores (0-100) from the open-label baseline to the end of treatment was -21 (30.5) in study 1 (1 year), -26.7 (28.8) in study 2 (12 weeks), and -20.1 (26.8) in study 3 (12 weeks). CONCLUSIONS: The data from these extension studies suggest that the adverse event safety profile and tolerability of patients with FM treated with open-label pregabalin (75-300 mg BID) for up to 1 year were stable and were consistent with those of previous studies. ClinicalTrials.gov identifiers: NCT00151528 (A0081057 [study 1]), NCT00282997 (A0081078 [study 2]), and NCT00346034 (A0081101 [study 3]).

Maraviroc, a chemokine receptor-5 antagonist, fails to demonstrate efficacy in the treatment of patients with rheumatoid arthritis in a randomized, double-blind placebo-controlled trial.

INTRODUCTION: The purpose of this study was to determine whether maraviroc, a human CC chemokine receptor 5 (CCR5) antagonist, is safe and effective in the treatment of active rheumatoid arthritis (RA) in patients on background methotrexate (MTX). METHODS: This phase IIa study comprised two distinct components: an open-label safety study of the pharmacokinetics (PK) of MTX in the presence of maraviroc, and a randomized, double-blind, placebo-controlled, proof-of-concept (POC) component. In the PK component, patients were randomized 1:1 to receive maraviroc 150 or 300 mg twice daily (BID) for four weeks. In the POC component, patients were randomized 2:1 to receive maraviroc 300 mg BID or placebo for 12 weeks. Patients were not eligible for inclusion in both components. RESULTS: Sixteen patients were treated in the safety/PK component. Maraviroc was well tolerated and there was no evidence of drug-drug interaction with MTX. One hundred ten patients were treated in the POC component. The study was terminated after the planned interim futility analysis due to lack of efficacy, at which time 59 patients (38 maraviroc; 21 placebo) had completed their week 12 visit. There was no significant difference in the number of ACR20 responders between the maraviroc (23.7%) and placebo (23.8%) groups (treatment difference -0.13%; 90% CI -20.45, 17.70; P = 0.504). The most common all-causality treatment-emergent adverse events in the maraviroc group were constipation (7.8%), nausea (5.2%), and fatigue (3.9%). CONCLUSIONS: Maraviroc was generally well tolerated over 12 weeks; however, selective antagonism of CCR5 with maraviroc 300 mg BID failed to improve signs and symptoms in patients with active RA on background MTX. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00427934.

Impact of a soluble phospholipase A2 inhibitor on inhaled allergen challenge in subjects with asthma.

The possible roles of secretory phospholipases A2 (sPLA2) in asthma include the release of arachidonic acid from cellular membranes, generation of lysophospholipids, sPLA2-mediated activation of cPLA2 with increased leukotriene production, and surfactant degradation. LY333013 is a potent inhibitor of sPLA2. This study examined the impact of two doses of LY333013 vs. placebo on allergen-induced bronchoconstriction following inhaled allergen challenge in atopic asthmatics. Fifty subjects were randomly assigned to treatment, and 40 subjects completed the study. A double-blind, placebo-controlled, random order, crossover study design was used. LY333013 had no impact on the primary outcome variables of the areas under the FEV1 response curve early (0-3 hours) (AUC(early)) and late (3-8 hours) (AUC(Iate)) following inhaled allergen challenge. No significant drug-related adverse effects were observed. The response to inhaled allergen challenge was reproducible and confirms the utility of this technique as a model in which to screen compounds for further testing in asthmatic patients.

LY315920NA/S-5920, a selective inhibitor of group IIA secretory phospholipase A2, fails to improve clinical outcome for patients with severe sepsis.

OBJECTIVE: Group IIA secretory phospholipase A2 (sPLA2-IIA), released during inflammation, is increased in severe sepsis, and plasma levels are inversely related to survival. In a previous study, a selective inhibitor of sPLA2-IIA (LY315920NA/S-5920) was well tolerated and appeared to improve survival in a subgroup of patients who received the drug within 24 hrs of first sepsis-induced organ failure. This study was designed to determine whether improvement in survival could be confirmed in a larger patient population meeting the characteristics of that subgroup. DESIGN: Multicenter, double-blind, placebo-controlled, parallel-group clinical trial of LY315920NA/S-5920 in patients with severe sepsis. SETTING: Seventy-five institutions worldwide. PATIENTS: A total of 373 patients with at least two sepsis-induced organ failures. INTERVENTIONS: Patients were randomized 1:1 to receive LY315920NA/S-5920 (target plasma concentration of 800 ng/mL; n = 188) or placebo (n = 185). Study medication was administered as a continuous intravenous infusion for 168 hrs. MEASUREMENTS AND MAIN RESULTS: The study was terminated after data on 250 patients suggested a significant improvement in 28-day all-cause mortality would not be found if the trial continued as planned. The mortality rate was 39.4% in the LY315920NA/S-5920 group, compared with 31.9% in the placebo group (p = .092). The negative trend in mortality was most pronounced among patients with cardiovascular failure at baseline (41.6% vs. 28.7%; p = .008) and patients whose culture data at baseline were negative (42.9% vs. 22.7%; p = .045). The negative trend in mortality is not explained by adverse events, microbiology, or laboratory data. CONCLUSIONS: Continuous 7-day infusion of an inhibitor of sPLA2-IIA had no beneficial effect on 28-day all-cause mortality among severe sepsis patients with at least two organ failures. This study did not confirm earlier promising subgroup results with LY315920NA/S-5920, which provides a reminder that subgroup effects should be viewed cautiously, especially when primary effects are not significant.

Neutrophil elastase and acute lung injury: prospects for sivelestat and other neutrophil elastase inhibitors as therapeutics.

OBJECTIVES: To review the evidence and rationale that suggest that neutrophil elastase (NE) may contribute to the development of acute lung injury (ALI) and the acute respiratory distress syndrome. To review selected preliminary data regarding the effectiveness of NE inhibition in animals, in in vitro models, and in patients with ALI. DATA SOURCES: The published literature and observations provided by Ono Pharmaceutical and Eli Lilly investigators and their colleagues. DATA SUMMARY: Taken en toto, the data suggest that NE could contribute to ALI and endothelial cell injury that is relevant to ALI. Moreover, the toxic effects of NE are greatly enhanced by increased oxidative stress, which commonly occurs in patients with ALI. In addition to neutrophils, xanthine oxidase, a constituent of endothelial cells, is a potential source of oxidative stress in ALI; xanthine oxidase-derived oxidants enhance NE toxicity in in vivo, isolated lung, and in vitro endothelial cell test systems. Not surprisingly, endogenous nonoxidatively sensitive NE inhibitors (e.g., eglin C) are more effective in combating the detrimental effects of NE than oxidatively sensitive NE inhibitors (e.g., alpha-1-proteinase inhibitor). In addition, a synthetic NE inhibitor, sivelestat (ONO-5046 and LY544349), is effective in reducing measures of inflammation and injury in multiple animal models of ALI. In a trial of ALI patients with systemic inflammatory response syndrome, conducted in Japan by Ono Pharmaceutical scientists, sivelestat treatment improved the investigator assessment of global improvement and the percentages of patients who were removed from ventilators and transferred out of the intensive care unit. CONCLUSIONS: Further study of the role of NE inhibition as a treatment for ALI is warranted. Additional clinical and preclinical studies with sivelestat and various other NE inhibitors should not only clarify the clinical potential of this intervention strategy, but also better define the activities of NE in inflammatory disorders such as ALI and multiple organ failure.

Neutrophil elastase inhibition in acute lung injury: results of the STRIVE study.

OBJECTIVE: Neutrophil elastase is believed to be an important mediator of acute lung injury. Sivelestat (ONO-5046, Elaspol) is a small molecular weight inhibitor of neutrophil elastase. The primary objectives of this study were to determine whether sivelestat would reduce 28-day all-cause mortality or increase the number of ventilator-free days (days alive and free from mechanical ventilation from day 1 to day 28) compared with placebo in mechanically ventilated patients with acute lung injury. DESIGN: Multiple-center, double-blind, placebo-controlled trial administering a continuous infusion of sivelestat at a dose of 0.16 mg.kg(-1)hr(-1). SETTING: One hundred and five institutions in the United States, Canada, Belgium, Spain, Australia, and New Zealand. PATIENTS: A total of 492 mechanically ventilated patients with acute lung injury. INTERVENTIONS: Patients were randomized in a 1:1 fashion to sivelestat or placebo. Study drug was administered as a continuous infusion for the duration of mechanical ventilation plus 24 hrs for a maximum of 14 days. All patients were managed using low tidal volume mechanical ventilation. MEASUREMENTS AND MAIN RESULTS: The study was stopped prematurely at the recommendation of an external Data and Safety Monitoring Board, which noted a negative trend in long-term mortality rate. Final analysis revealed no effect of sivelestat on the primary end points of ventilator-free days (day 1-day 28) or 28-day all-cause mortality. There were 64 deaths in each treatment group within the 28-day study period, and the mean number of ventilator-free days was 11.4 and 11.9 in the sivelestat and placebo treatment groups, respectively (p =.536). There was no evidence of effect on measures of pulmonary function, including Pao2/Fio2, static lung compliance, and time to meeting weaning criteria. There was no difference in adverse events or serious adverse events between treatment groups. A comparison of the Kaplan-Meier 180-day survival curves showed no difference between treatment groups (p =.102), but there was an increase in 180-day all-cause mortality in the sivelestat treatment group compared with the placebo group (p =.006). CONCLUSIONS: Intravenous sivelestat had no effect on 28-day all-cause mortality or ventilator-free days in a heterogeneous acute lung injury patient population managed with low tidal volume mechanical ventilation.