系统评价IL-12/23单克隆抗体治疗斑块状银屑病发生严重心血管事件的风险

目的:系统评价IL-12/23单克隆抗体治疗斑块状银屑病发生严重心血管事件的风险.方法:系统检索PubMed,Em-base,CENTRAL,CNKI,VIP,WangFang等数据库以及ClinicalTrials.gov网站,搜集IL-12/23单克隆抗体治疗斑块状银屑病的RCTs,检索时间为从数据库建库至2020...     

A phase I trial of an interleukin‐12/23 monoclonal antibody in relapsing multiple sclerosis

ABSTRACT

Objective: To assess the safety, tolerability and pharmacokinetics of an interleukin (IL)-12/23 monoclonal antibody (mAb) in subjects with a relapsing form of multiple sclerosis (MS).

Methods: A phase I, double-blind, placebo-controlled, sequential dose escalation study was conducted in 20 subjects with MS. Subjects were randomized (4:1) to receive a single subcutaneous injection of either IL‐12/23 mAb (0.3, 0.75, 1.5, and 3.0?mg/kg) or placebo. Clinical and laboratory evaluations were performed through 16 weeks following administration.

Results: IL‐12/23 mAb was well tolerated in this study. Adverse events were generally mild or moderate, with no apparent dose-related trends. One subject with a family history of breast cancer was diagnosed during the study with breast cancer 21 days after IL‐12/23 mAb administration. There were no significant changes in laboratory indicators of systemic or neurotoxicity. There was a large degree of variability in T2 lesion volume and total number of gadolinium-positive lesions, both unaffected by dose escalation. Three relapses of MS occurred in two placebo-treated subjects. Over the range of single doses studied, the median T_max ranged from 9.0 to 16.5 days, and the median T_1/2 ranged from 20.2 to 30.9 days.

Conclusion: Single subcutaneous administrations of IL‐12/23 mAb in this first study of relapsing MS were generally well tolerated. Safety of the agent will need to be tested in a study of longer duration and involving a larger cohort of subjects.     

A phase I trial of an interleukin-12/23 monoclonal antibody in relapsing multiple sclerosis

OBJECTIVE: To assess the safety, tolerability and pharmacokinetics of an interleukin (IL)-12/23 monoclonal antibody (mAb) in subjects with a relapsing form of multiple sclerosis (MS). METHODS: A phase I, double-blind, placebo-controlled, sequential dose escalation study was conducted in 20 subjects with MS. Subjects were randomized (4:1) to receive a single subcutaneous injection of either IL-12/23 mAb (0.3, 0.75, 1.5, and 3.0 mg/kg) or placebo. Clinical and laboratory evaluations were performed through 16 weeks following administration. RESULTS: IL-12/23 mAb was well tolerated in this study. Adverse events were generally mild or moderate, with no apparent dose-related trends. One subject with a family history of breast cancer was diagnosed during the study with breast cancer 21 days after IL-12/23 mAb administration. There were no significant changes in laboratory indicators of systemic or neurotoxicity. There was a large degree of variability in T2 lesion volume and total number of gadolinium-positive lesions, both unaffected by dose escalation. Three relapses of MS occurred in two placebo-treated subjects. Over the range of single doses studied, the median Tmax ranged from 9.0 to 16.5 days, and the median T1/2 ranged from 20.2 to 30.9 days. CONCLUSION: Single subcutaneous administrations of IL-12/23 mAb in this first study of relapsing MS were generally well tolerated. Safety of the agent will need to be tested in a study of longer duration and involving a larger cohort of subjects.     

A role for CB2 receptors in anandamide signalling pathways involved in the regulation of IL-12 and IL-23 in microglial cells

The endocannabinoid system represents a novel therapeutic target for autoimmune and chronic inflammatory diseases. IL-12 and IL-23 are functionally related heterodimeric cytokines that play a crucial role in the pathogenesis of multiple sclerosis (MS). In the present study we investigated the effects of the endocannabinoid anandamide (AEA) on the inducible expression of the biologically active cytokines IL-12p70 and IL-23, and their forming subunits, in activated microglial cells. We also studied the signalling pathways involved in the regulation of IL-12p70/IL-23 expression and addressed the possible interactions of AEA with these pathways. Here, we show that AEA was capable to inhibit the production of biologically active IL-12p70 and IL-23, and their subunits, by activated human and murine microglial cultures. Treatment of activated microglial cells with inhibitors of several mitogen-activated protein kinase (MAPK) reveals that AEA acts through the ERK1/2 and JNK pathways to down-regulate IL-12p70 and IL-23. These effects were partially mediated by CB2 receptor activation. Together, our results provide the first demonstration of a role of AEA in inhibiting IL-12p70/IL-23 axis in human and murine microglial cells via the CB2 receptor and suggest that the pharmacological manipulation of the endocannabinoid system is a potential tool for treating brain inflammatory and autoimmune diseases, like MS.     

Evaluation of safety and human tolerance of the oral probiotic Streptococcus salivarius K12: A randomized, placebo-controlled, double-blind study

Streptococcus salivarius is naturally a predominant member of the human oropharynx and the commercial probiotic strain K12 has been consumed for more than a decade. The present study examines the health responses of human volunteers to oral ingestion of high doses of S. salivarius K12.A randomized group of 53 subjects received a dose of 1 × 10¹⁰ cfu S. salivarius K12 (N = 25) or placebo (N = 28) for 28 days, followed by a 28-day wash out period. Blood, urine and saliva samples were collected at baseline and following treatment and analyzed, while the oral and gastrointestinal tolerance of the subjects to the dosing regimen was determined by use of questionnaires. Adverse events (AE)s were recorded for both groups.No statistically significant differences between the probiotic and placebo treated groups were detected in either the blood clinical chemistry or hematology results (P > 0.05). The questionnaire responses of the subjects indicated that both treatments were well tolerated. The frequency and intensity of AEs was similar in the two groups.This data demonstrates that the daily ingestion of S. salivarius K12 over a 28-day period does not adversely affect the human host and supports the safety of its oral delivery in a food-based carrier.     

A phase II,randomized, placebo-controlled,double-blind,multi-dose study of SRT2104, a SIRT1 activator,in subjects with type 2 diabetes

Aim

SRT2104 is a selective activator of SIRT1. In animal models, SRT2104 improves glucose homeostasis and increases insulin sensitivity. We evaluated the tolerability and pharmacokinetics of SRT2104, and its effects on glycaemic control, in adults with type 2 diabetes mellitus.

Method

Type 2 diabetics with glycosylated haemoglobin (HbA1c) ≥ 7.5% and ≤10.5%, fasting glucose ≥160 and ≤240 mg dl⁻¹, and on stable doses of metformin were evenly randomized to placebo or SRT2104 0.25 g, 0.5 g, 1.0 g or 2.0 g, administered orally once daily for 28 days. Changes in fasting and post-prandial glucose and insulin were analyzed.

Results

Safety evaluation found no major differences between groups in the frequency of adverse events. SRT2104 concentrations did not increase in a dose-proportional fashion. Significant variability in exposure was observed. Treatment with SRT2104 did not lead to any consistent, dose-related changes in glucose or insulin. Day 28 change from baseline (mean (SD)): fasting glucose (mmol l⁻¹) = −1.17 (2.42), −1.11 (3.45), −0.52 (2.60), −0.97 (2.83) and −0.15 (2.38) for placebo, 0.25 g, 0.5 g, 1.0 g and 2.0 g, respectively. Day 28 change from baseline (mean (SD)): fasting insulin (mmol l⁻¹) = 1.0 (51.66), 8.9 (95.04), −6.9 (41.45), 4.1 (57.16) and 15.2 (138.79) for placebo, 0.25 g, 0.5 g, 1.0 g and 2.0 g, respectively) Treatment with SRT2104 was associated with improvement in lipid profiles.

Conclusion

Treatment with SRT2104 for 28 days did not result in improved glucose or insulin control which is likely due to the observed pharmacokinetics which were not dose proportional and had large between subject variability.     

A phase 1, placebo-controlled,randomised, double-blind (within dose panels) study evaluating the safety,tolerability and pharmacokinetics of intravenous NXY-059 in Japanese subjects

ABSTRACT

Objective: NXY?059 has a proposed mechanism of action of free-radical trapping and has been studied in clinical trials based on positive effects seen in experimental models of acute ischaemic stroke. This study evaluated the safety, tolerability and pharmacokinetics of NXY?059 in healthy Japanese male subjects compared with previous data from healthy Caucasian subjects.

Research design and methods: The primary objective of this phase 1, double-blind, randomised, placebo-controlled, dose-escalating study was to evaluate the safety and tolerability of an 8- or 24?h intravenous infusion of NXY-059 targeting an unbound plasma concentration of 25–300?μmol/L in healthy Japanese male subjects (20–45 years). NXY?059 pharmacokinetics were also assessed, and any differences in pharmacokinetics between Japanese and previously studied Caucasian subjects (20–45 years) were explored.

Results: NXY?059 was generally well tolerated and no safety concerns were identified. There was a similar incidence of adverse events between subjects receiving NXY?059 or placebo, and no obvious trend towards an increased incidence of adverse events with increasing doses of NXY?059 was observed. In addition, there was no evidence of any vasoirritative effects or changes in renal function. The tolerability profile was similar in Caucasian subjects. The pharmacokinetic results indicate proportional exposure of 8?h and 24?h infusions of NXY?059 resulting in mean unbound steady state plasma concentrations up to 417?μmol/L and 379?μmol/L, respectively. Plasma clearance values for NXY?059 were similar in both Japanese and Caucasian subjects.

Conclusions: This study suggests that the tolerability and pharmacokinetics of NXY?059 in healthy Japanese male subjects and Caucasians are similar.     

A randomized,placebo-controlled,single ascending-dose study to assess the safety,tolerability, pharmacokinetics,and immunogenicity of subcutaneous tralokinumab in Japanese healthy volunteers

Tralokinumab is a human monoclonal antibody in clinical development for asthma and atopic dermatitis that specifically neutralizes interleukin-13. This phase I, single-blind, randomized, placebo-controlled, single ascending-dose study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of subcutaneous tralokinumab (150, 300, or 600 mg) in thirty healthy Japanese adults. The most frequent treatment-emergent adverse event (TEAE) in all treatment groups was injection-site pain. The frequency and severity of TEAEs was similar across tralokinumab doses. C_max, AUC_(0–t), and AUC_(0–inf) increased in a dose-proportional manner, and mean t_1/2 ranged from 20 to 25 days. No anti-drug antibodies were detected. A post-hoc pooled population PK modeling analysis, incorporating PK data from this study, demonstrated that Japanese individuals had greater systemic exposure to tralokinumab than non-Japanese individuals. This difference was not clinically relevant and was primarily due to differences in body weight, with lower body weight associated with greater PK exposure. Japanese ethnicity was not a significant predictor of tralokinumab PK. This study indicates that single-dose subcutaneous administration of tralokinumab 150–600 mg was well tolerated in Japanese healthy volunteers, and supports the 300 mg dose selection for Japanese patients with asthma in ongoing clinical trials.     

Clinical trial: a multicentre, randomized, double-blind, placebo-controlled, dose-finding, phase II study of subcutaneous interferon-β-1a in moderately active ulcerative colitis

Background  Ulcerative colitis (UC) pathophysiology is characterized by an imbalance between pro- and anti-inflammatory cytokines. Interferon (IFN)-β-1a has potent immunoregulatory properties, including stimulation of host defence mechanisms and thus represents a potential treatment.
Aim  To extend pilot data and identify a suitable dose of IFN-β-1a to achieve endoscopically confirmed remission (ECR) in patients with moderately active UC and to evaluate safety.
Methods  In this multicentre, double-blind, placebo-controlled trial, adults with moderately active UC were randomized to IFN-β-1a 44 or 66 μg, or placebo, subcutaneously three times weekly for 8 weeks, with a 4-week follow-up.
Results  Endoscopically-confirmed remission was observed in 23.4% [95% confidence interval (CI): 13.8–35.7] of placebo patients, 29.2% (95% CI: 18.6–41.8) of the IFN-β-1a 44 μg group and 20.0% (95% CI: 11.1–31.8) of the 66 μg group ( P  = 0.45). Improvements with IFN-β-1a 44 μg were greater than with placebo for most secondary efficacy outcomes, although significance was not achieved. Placebo response rates were higher than expected from previous trials. Adverse events were similar to the known safety profile of IFN treatment.
Conclusions  Interferon-β-1a was generally well tolerated at the doses tested, but a significant therapeutic benefit in patients with UC was not observed.     

A phase II dose ranging, double-blind, placebo-controlled study of alicaforsen enema in subjects with acute exacerbation of mild to moderate left-sided ulcerative colitis

BACKGROUND: Alicaforsen is an antisense oligonucleotide designed to inhibit expression of human intercellular adhesion molecule 1. Previous clinical studies have demonstrated activity of alicaforsen enema in ulcerative colitis and pouchitis. AIM: To determine the minimally effective dosing regimen of alicaforsen enema in subjects with mild to moderate left-sided ulcerative colitis. METHODS: Randomized, placebo-controlled, double-blind, two-dose ranging multicentre study. One hundred and twelve subjects were equally randomized to receive one of four alicaforsen enema regimens or placebo daily for 6 weeks. Primary end point was Disease Activity Index at week 6. Secondary end points included evaluation of clinical improvement, relapse rates and durability of response. Analysis of data were performed on the intent-to-treat population. RESULTS: No significant difference was observed between treatment arms and placebo in the primary end point. A prolonged reduction in mean% Disease Activity Index relative to baseline was observed in the daily 240 mg alicaforsen enema treatment arm in comparison with placebo from week 18 (51% vs. 18%, P=0.04) to week 30 (50% vs. 11%, P=0.03). CONCLUSIONS: Alicaforsen enema was safe and well tolerated at all doses studied. The durability of the response to alicaforsen enema treatment may suggests a disease-modifying effect.     

A randomized, double-blind, placebo-controlled trial of CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, in patients with corticosteroid-dependent Crohn's disease

AIM: To evaluate CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, for the treatment of corticosteroid-dependent Crohn's disease. METHODS: Patients with corticosteroid-dependent Crohn's disease (use of prednisolone 15-40 mg/day or budesonide 9 mg/day for at least 8 weeks, a previous failed attempt to discontinue corticosteroids within 8 weeks, and Crohn's Disease Activity Index score 150 points or less) were enrolled in a 16-week, randomized, double-blind, placebo-controlled trial. The patients received intravenous CDP571 (20 mg/kg at week 0 and 10 mg/kg at week 8) or placebo. Corticosteroid therapy was decreased following a predefined schedule. The primary efficacy end-point was the percentage of patients with corticosteroid-sparing [i.e. no disease flare (Crohn's Disease Activity Index score > or =220 points) and no longer requiring corticosteroid therapy] at week 10. The major secondary efficacy end-point was corticosteroid-sparing at week 16. RESULTS: Seventy-one patients received treatment. Corticosteroid-sparing was achieved by 19 of 39 (48.7%) CDP571 patients and 13 of 42 (40.6%) placebo patients (P = 0.452) at week 10, and by 18 of 39 (46.2%) CDP571 patients and seven of 32 (21.9%) placebo patients (P = 0.032) at week 16. CDP571 therapy was well-tolerated and the incidence of serious adverse events was similar to placebo. CONCLUSIONS: The CDP571 was effective for corticosteroid-sparing at week 16 but not week 10, and was well-tolerated in patients with corticosteroid-dependent Crohn's disease.     

Tolerability, pharmacokinetics and pharmacodynamics of the once-daily human GLP-1 analog liraglutide in Japanese healthy subjects: a randomized, double-blind, placebo-controlled dose-escalation study

OBJECTIVES: Liraglutide is a once-daily human GLP-1 analog being developed as a Type 2 diabetes therapy. A dose-finding study in Japanese patients with Type 2 diabetes showed liraglutide to produce dose-dependent decreases in HbA(1C). Studies have also shown that, with stepped dose titration, liraglutide is well tolerated. This double-blind trial in 24 healthy Japanese men assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of once-daily subcutaneous (s.c.) liraglutide using doses exceeding those previously studied, and using the stepped titration approach. MATERIALS AND METHODS: Subjects were randomized to three groups in each of which 6 received liraglutide, and 2 placebo for 35 consecutive days. The daily dose of liraglutide was stepped from 5 microg/kg (s.c. abdomen, morning) to 10 and then 15 microg/kg at 7-day intervals. One group remained at this dose, the others titrating further to 20 and 25 microg/kg, respectively. Subjects remained at the study site from Day 21 until the end of the trial, with standard meals served during inhouse periods. RESULTS: No safety issues, hypoglycemia, gastrointestinal or any other adverse events were observed. Liraglutide showed dose-dependent increases in the pharmacokinetic parameters of AUC0-24 h, C(max) and C(trough), while t(max), t(1/2) and V(d/F) were constant. Mean plasma glucose concentrations were similar across all treatment groups at baseline, but dose-dependent decreases in mean and postprandial plasma glucose were seen with liraglutide, although all values remained within normal ranges. There was a tendency for weight to decrease with liraglutide in comparison to placebo. CONCLUSIONS: Liraglutide appears to be well tolerated at doses of up to 25 microg/kg in Japanese subjects. Despite clear pharmacodynamic effects in this euglycemic cohort, a low risk for hypoglycemia was suggested together with good gastrointestinal tolerability.