Safety, tolerability and pharmacokinetic characterisation of DACRA KBP-042 in healthy male subjects.

There is a need for antidiabetic agents successfully targeting insulin sensitivity and treating obesity control at the same time. The aim of this first-in-human study was (a) to evaluate safety and tolerability, (b) to evaluate pharmacokinetics and (c) to assess indications of receptor engagement of single ascending doses of KBP-042, a dual amylin and calcitonin receptor agonist (DACRA) that has shown promising preclinical data, with superior activity in terms of typical amylin-induced responses including reduction of food intake, weight loss and gluco-regulatory capacities. A randomised double-blind placebo-controlled single ascending dose study was performed with six dose levels of KBP-042 (5, 7.5, 10, 20, 20 (evening), 40 ug) in healthy male adults. KBP-042 or placebo was administered as a single dose after an overnight fast, followed by a standardized lunch after 4 hours. KBP-042 was associated with dose-dependent complaints of nausea and vomiting, with a lack of tolerability at doses of 20 µg and above. Doses of 5-40 µg KBP-042 behaved according to a linear pharmacokinetic profile. Indications of target receptor engagement were observed at the level of glucose control and lowering of bone resorption, compared to placebo. The results of this study showed that doses up to 40 µg were safe, although tolerability was not present at the highest doses. The study confirmed target receptor engagement at the studied doses.

Characterization of immune cell, endothelial, and renal responses upon experimental human endotoxemia.

INTRODUCTION: Although the effects of relatively high concentrations of endotoxin on endothelial activation/dysfunction and kidney markers has been described in literature, detailed insight in the LPS concentration-effect relationship, the magnitude, variability and timing of the response, and potential effects of endotoxemia on the kidneys is lacking. A study was performed to assess the effects of low- to moderate dose (0.5, 1 or 2ng/kg) endotoxemia on the endothelium and kidneys as measured by a panel of novel highly sensitive kidney injury markers. METHODS: This was a randomized, double-blind, placebo-controlled study with single ascending doses of LPS (0.5, 1 or 2ng/kg) administered to healthy male volunteers (3 cohorts of 8 subjects, LPS:placebo 6:2). Endothelial measures included selectins, cell adhesion molecules, and thrombomodulin. Renal measures included novel, sensitive and specific biomarkers of acute kidney injury. RESULTS: Endotoxin exposure resulted in consistent LPS dose-dependent responses in inflammatory markers, E- and P- Selectin, VCAM1, ICAM1, and thrombomodulin. The observed biological responses were transient, reaching a level of significance of at least <0.01 in the highest dose group and with an effect size which was dependent on the administered LPS dose. LPS-induced inflammatory and endothelial effects did not translate into a change in renal damage biomarkers, although at 2ng/kg LPS, subtle and transient biomarker changes were observed that may relate to (subclinical) tubular damage. DISCUSSION: We demonstrated that administration of a single LPS dose of 2ng/kg to healthy volunteers results in significant inflammatory and endothelial responses, without inducing clinically relevant signs of kidney injury. These findings support the application of the human endotoxemia model in future clinical pharmacology studies.

Clinical Evaluation of Humira® Biosimilar ONS-3010 in Healthy Volunteers: Focus on Pharmacokinetics and Pharmacodynamics.

ONS-3010 is being developed by Oncobiologics Inc. (Cranbury, NJ, USA) as a biosimilar of Humira®. This randomized, double blind, single-center phase I study (EudraCT registration # 2013-003551-38) was performed to demonstrate pharmacokinetic (PK) biosimilarity between two reference products (Humira® EU and US) and ONS-3010 in healthy volunteers, and to compare the safety and immunogenicity profiles. In addition, the intended pharmacological activity was assessed and compared by application of a whole blood challenge. Hundred ninety-eight healthy volunteers received a single 40 mg subcutaneous dose of ONS-3010, Humira® EU, or US. The pharmacodynamic effects were assessed by lipopolysaccharide (LPS)/aluminum hydroxide whole blood challenges (n = 36; n = 12 per treatment arm; male:female, 1:1). Equivalence was demonstrated on the PK endpoints (AUC0-inf, Cmax, and AUC0-last) based on bounds of 80-125% for the ratio of the geometric means (ONS-3010/Humira®). The immunogenicity profiles were comparable between treatment groups, and there were no indications for differences in routine safety parameters. Administration of adalimumab resulted in the observation of dramatically reduced tumor necrosis factor-α (TNFα) levels upon stimulation with LPS/aluminum hydroxide (>99%), with no differences between the three treatment groups in terms of magnitude or duration. Adalimumab also resulted in a reduction of LPS/aluminum hydroxide-induced interleukin (IL)-8 release (maximally 30%), suggested to have a causal relationship with the anti-TNFα treatment. LPS/aluminum hydroxide-induced release of IL-1ß and IL-6 was not inhibited by anti-TNFα treatment. Taken together, these data are promising for the further clinical development of ONS-3010, demonstrate the relevance of the LPS/aluminum challenge to monitor Humira® effects, and emphasize the value of whole blood challenges for monitoring of proximal drug effects in healthy volunteers, and potentially in the target population.

Recombinant human pentraxin-2 therapy in patients with idiopathic pulmonary fibrosis: safety, pharmacokinetics and exploratory efficacy.

Abnormal fibrogenic repair response upon alveolar injury is believed to play an important role in the pathogenesis of idiopathic pulmonary fibrosis (IPF). PRM-151 (recombinant human pentraxin-2, also known as serum amyloid P), has been shown to reduce fibrosis in preclinical lung fibrosis models, and was well tolerated with a favourable pharmacokinetic profile in an earlier single-dose phase I study.A randomised, double-blind, placebo-controlled, multiple ascending dose trial was performed to assess the tolerability and pharmacokinetic and pharmacodynamic characteristics of multiple doses of PRM-151 in IPF patients. Subjects in three successive cohorts (1, 5, or 10 mg·kg(-1) versus placebo) received intravenous study drug on days 1, 3, 5, 8 and 15, and were followed-up to day 57.PRM-151 was well tolerated at all dose levels, with no serious adverse reactions. Administration of PRM-151 resulted in two- to eight-fold dose-dependent increases in circulating pentraxin-2 levels. Forced vital capacity and 6-min walk test showed trends towards improvement in the combined PRM-151 dose groups. On high-resolution computed tomography scans, stable or improved lung volume unoccupied by interstitial lung abnormality was noted in some PRM-151 subjects compared to placebo subjects on day 57.The efficacy of PRM-151 in IPF remains to be investigated in dedicated future trials.