Endothelial-protective effects of a G-protein-biased sphingosine-1 phosphate receptor-1 agonist, SAR247799, in type-2 diabetes rats and a randomized placebo-controlled patient trial.

Aims: SAR247799 is a G-protein-biased sphingosine-1 phosphate receptor-1 (S1P ) agonist designed to activate endothelial S1P and provide endothelial-protective properties, while limiting S1P desensitization and consequent lymphocyte-count reduction associated with higher doses. The aim was to show whether S1P activation can promote endothelial effects in patients and, if so, select SAR247799 doses for further clinical investigation.

Methods: Type-2 diabetes patients, enriched for endothelial dysfunction (flow-mediated dilation, FMD <7%; n = 54), were randomized, in 2 sequential cohorts, to 28-day once-daily treatment with SAR247799 (1 or 5 mg in ascending cohorts), placebo or 50 mg sildenafil (positive control) in a 5:2:2 ratio per cohort.

First-in-human study of the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple oral doses of SAR247799, a selective G-protein-biased sphingosine-1 phosphate receptor-1 agonist for endothelial protection.

Aims: SAR247799 is a selective G-protein-biased sphingosine-1 phosphate receptor-1 (S1P ) agonist with potential to restore endothelial function in vascular pathologies. SAR247799, a first-in-class molecule differentiated from previous S1P -desensitizing molecules developed for multiple sclerosis, can activate S1P without desensitization and consequent lymphopenia. The aim was to characterize SAR247799 for its safety, tolerability, pharmacokinetics and pharmacodynamics (activation and desensitization).

A Pilot Study to Assess the Feasibility of Collecting and Transmitting Clinical Trial Data with Mobile Technologies.

Background: The use of mobile technologies for data capture and transmission has the potential to streamline clinical trials, but researchers lack methods for collecting, processing, and interpreting data from these tools.

Objectives: To assess the performance of a technical platform for collecting and transmitting data from six mobile technologies in the clinic and at home, to apply methods for comparing them to clinical standard devices, and to measure their usability, including how willing subjects were to use them on a regular basis.

Methods: In part 1 of the study, conducted over 3 weeks in the clinic, we tested two device pairs (mobile vs.

Dupilumab in persistent asthma with elevated eosinophil levels.

Background: Moderate-to-severe asthma remains poorly treated. We evaluated the efficacy and safety of dupilumab (SAR231893/REGN668), a fully human monoclonal antibody to the alpha subunit of the interleukin-4 receptor, in patients with persistent, moderate-to-severe asthma and elevated eosinophil levels.

Methods: We enrolled patients with persistent, moderate-to-severe asthma and a blood eosinophil count of at least 300 cells per microliter or a sputum eosinophil level of at least 3% who used medium-dose to high-dose inhaled glucocorticoids plus long-acting beta-agonists (LABAs).

Effect of IVL745, a VLA-4 antagonist, on allergen-induced bronchoconstriction in patients with asthma.

Background: Very late antigen (VLA-4) antagonists have been proposed as potential therapies for diseases in which cell recruitment and accumulation are causative. Asthma, which is characterized by airway inflammation involving the accumulation of eosinophils and mononuclear cells, is one such disease.

Objective: We sought to assess the effect of IVL745, a VLA-4 antagonist, on the early and late asthmatic response (LAR) and on markers of airway inflammation after allergen inhalation.

Pharmacokinetics, pharmacodynamics, and safety of a lipid-lowering adenosine A1 agonist, RPR749, in healthy subjects.

RPR749 and its methylated metabolite are orally active and selective adenosine A(1) agonists that can inhibit lipolysis and lower plasma triglyceride levels in a variety of animal models. RPR749 also appears to lower free fatty acid (FFA) and insulin levels and may have additional lipid-modifying effects. This double-blind, single increasing-dose, placebo-controlled, parallel group, randomized study, the first done in humans, evaluated the safety, pharmacokinetics, and pharmacodynamics (effect on FFA) after a single oral dose of up to 200 mg RPR749 or placebo.

Estimating mass balance for inhaled drugs in humans: an example with a VLA-4 antagonist, IVL745.

IVL745 is an inhaled VLA-4 antagonist developed for the treatment of asthma. Following inhalation (Inh), a fraction of the drug is deposited in the oropharynx, and the rest is deposited in the lungs. For inhaled drugs, it is technically and ethically difficult to formulate and administer radiolabeled drugs.

Pharmacoscintigraphic comparison of HMR 1031, a VLA-4 antagonist, in healthy volunteers following delivery via a nebulizer and a dry powder inhaler.

A pharmacoscintigraphic study was conducted to compare the dose deposition of HMR 1031 from the existing nebulizer formulation and the new Ultrahaler device to help determine the doses for future phase 2 trials. This was a single-dose, open-label, randomized, two-way crossover study in which HMR 1031 (3 mg) was delivered by the Ultrahaler and the Pari LC Star nebulizer to 12 healthy male subjects. For both treatments, the formulations were radiolabeled with technetium-99m pertechnetate such that a maximum of 10 MBq was delivered on each study day.