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.
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). We administered dupilumab (300 mg) or placebo subcutaneously once weekly. Patients were instructed to discontinue LABAs at week 4 and to taper and discontinue inhaled glucocorticoids during weeks 6 through 9. Patients received the study drug for 12 weeks or until a protocol-defined asthma exacerbation occurred. The primary end point was the occurrence of an asthma exacerbation; secondary end points included a range of measures of asthma control. Effects on various type 2 helper T-cell (Th2)-associated biomarkers and safety and tolerability were also evaluated.
A total of 52 patients were assigned to the dupilumab group, and 52 patients were assigned to the placebo group. Baseline characteristics were similar in the two groups. Three patients had an asthma exacerbation with dupilumab (6%) versus 23 with placebo (44%), corresponding to an 87% reduction with dupilumab (odds ratio, 0.08; 95% confidence interval, 0.02 to 0.28; P<0.001). Significant improvements were observed for most measures of lung function and asthma control. Dupilumab reduced biomarkers associated with Th2-driven inflammation. Injection-site reactions, nasopharyngitis, nausea, and headache occurred more frequently with dupilumab than with placebo.
In patients with persistent, moderate-to-severe asthma and elevated eosinophil levels who used inhaled glucocorticoids and LABAs, dupilumab therapy, as compared with placebo, was associated with fewer asthma exacerbations when LABAs and inhaled glucocorticoids were withdrawn, with improved lung function and reduced levels of Th2-associated inflammatory markers. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT01312961.).
Aims
SAR247799 is a selective G‐protein‐biased sphingosine‐1 phosphate receptor‐1 (S1P1) agonist with potential to restore endothelial function in vascular pathologies. SAR247799, a first‐in‐class ...molecule differentiated from previous S1P1‐desensitizing molecules developed for multiple sclerosis, can activate S1P1 without desensitization and consequent lymphopenia. The aim was to characterize SAR247799 for its safety, tolerability, pharmacokinetics and pharmacodynamics (activation and desensitization).
Methods
SAR247799 was administered orally to healthy subjects in a double‐blind, randomized, placebo‐controlled study with single (2.5–37.5 mg) or 2‐week once‐daily (0.5–15 mg) doses. An open‐label single dose pilot food‐interaction arm with 10 mg SAR247799 in cross‐over design was also performed.
Results
SAR247799 was well tolerated and, at the higher end of the dose ranges, caused the expected dose‐dependent pharmacodynamics associated with S1P1 activation (heart rate reduction) and S1P1 desensitization (lymphocyte count reduction). SAR247799 demonstrated dose‐proportional increases in exposure and was eliminated with an apparent terminal half‐life of 31.2–33.1 hours. Food had a small effect on the pharmacokinetics of SAR247799. SAR247799 had a low volume of distribution (7–23 L), indicating a potential to achieve dose separation for endothelial vs cardiac S1P1 activation pharmacology. A supratherapeutic dose (10 mg) of SAR247799 produced sustained heart rate reduction over 14 days, demonstrating cardiac S1P1 activation without tachyphylaxis. Sub‐lymphocyte‐reducing doses (≤5 mg) of SAR247799, which, based on preclinical data, are projected to activate S1P1 and exhibit endothelial‐protective properties, had minimal‐to‐no heart rate reduction and displayed no marked safety findings.
Conclusion
SAR247799 is suitable for exploring the biological role of endothelial S1P1 activation without causing receptor desensitization.
Aims
SAR247799 is a G‐protein‐biased sphingosine‐1 phosphate receptor‐1 (S1P1) agonist designed to activate endothelial S1P1 and provide endothelial‐protective properties, while limiting S1P1 ...desensitization and consequent lymphocyte‐count reduction associated with higher doses. The aim was to show whether S1P1 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. Endothelial function was assessed by brachial artery FMD. Renal function, biomarkers and lymphocytes were measured following 5‐week SAR247799 treatment (3 doses) to Zucker diabetic fatty rats and the data used to select the doses for human testing.
Results
The maximum FMD change from baseline vs placebo for all treatments was reached on day 35; mean differences vs placebo were 0.60% (95% confidence interval CI −0.34 to 1.53%; P = .203) for 1 mg SAR247799, 1.07% (95% CI 0.13 to 2.01%; P = .026) for 5 mg SAR247799 and 0.88% (95% CI −0.15 to 1.91%; P = .093) for 50 mg sildenafil. Both doses of SAR247799 were well tolerated, did not affect blood pressure, and were associated with minimal‐to‐no lymphocyte reduction and small‐to‐moderate heart rate decrease.
Conclusion
These data provide the first human evidence suggesting endothelial‐protective properties of S1P1 activation, with SAR247799 being as effective as the clinical benchmark, sildenafil. Further clinical testing of SAR247799, at sub‐lymphocyte‐reducing doses (≤5 mg), is warranted in vascular diseases associated with endothelial dysfunction.
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. clinical standard blood pressure monitor and mobile vs. clinical standard spirometer) on 25 healthy volunteers. In part 2 of the study, conducted over 3 days both in the clinic and at home, we tested the same two device pairs as in part 1, plus four additional pairs (mobile vs. clinical standard pulse oximeter, glucose meter, weight scale, and activity monitor), on 22 healthy volunteers. Results: Data collection reliability was 98.1% in part 1 of the study and 95.8% in part 2 (the percentages exclude the wearable activity monitor, which collects data continuously). In part 1, 20 of 1,049 overall expected measurements were missing (1.9%), and in part 2, 45 of 1,083 were missing (4.2%). The most common reason for missing data was a single malfunctioning spirometer (13 of 20 total missed readings) in part 1, and that the subject did not take the measurement (22 of 45 total missed readings) in part 2. Also in part 2, a higher proportion of at-home measurements than in-clinic readings were missing (12.6 vs. 2.7%). The data from this experimental study were unable to establish repeatability or agreement for every mobile technology; only the pulse oximeter demonstrated repeatability, and only the weight scale demonstrated agreement with the clinical standard device. Most mobile technologies received high “willingness to use” ratings from the patients on the questionnaires. Conclusions: This study demonstrated that the wireless data transmission and processing platform was dependable. It also identified three critical areas of study for advancing the use of mobile technologies in clinical research: (1) if a mobile technology captures more than one type of endpoint (such as blood pressure and pulse), repeatability and agreement may need to be established for each endpoint to be included in a clinical trial; (2) researchers need to develop criteria for excluding invalid device readings (to be identified by algorithms in real time) for the population studied using ranges based on accumulated subject data and established norms; and (3) careful examination of a mobile technology’s performance (reliability, repeatability, and agreement with accepted reference devices) during pilot testing is essential, even for medical devices approved by regulators.
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.
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.
The study was of a placebo-controlled, double-blind, randomized, 2-way crossover design. Sixteen subjects with mild-to-moderate asthma controlled with short-acting β
2-agonists only and with a LAR to inhaled allergen participated in the study. At one treatment period they took 20 mg of IVL745 and one treatment period placebo. Both treatments were taken twice daily for 7 days, with a single dose on day 8. Treatments were separated by a washout period of at least 2 weeks. On day 7 of each treatment period, sputum was induced and collected, and exhaled nitric oxide (NO) was measured. On day 8, an inhaled bolus allergen challenge was performed, and blood was taken for pharmacokinetics. On day 9, exhaled NO was measured, and a methacholine challenge was done. On day 10, sputum was induced and collected. Adverse events, peak expiratory flow (PEF), use of short-acting β
2-agonists, and asthma symptoms were recorded daily throughout the study.
There was no statistically significant difference between IVL745 and placebo in the effect on the LAR after allergen challenge, as measured by the area under the curve of the percentage change in FEV
1 from the prechallenge baseline (mean SEM, −81.99 18.80 after IVL745 and −72.58 21.29 after placebo; 95% CI of difference, −36 to 16.8;
P = .46) or by the maximum percentage change from the prechallenge baseline (mean SEM, −23.44 4.73 after IVL745 and −21.30 5.17 after placebo; 95% CI of difference, −11 to 6.29;
P = .60). There was a statistically significant decrease in the percentage of eosinophils in sputum on day 7 of treatment with IVL745 (mean SEM, 7.32 1.46) compared with placebo (mean SEM, 15.00 1.92; 95% CI of difference, −13 to −1.2;
P = .02). There was no statistically significant difference between IVL745 and placebo with respect to the early asthmatic response, methacholine hyperresponsiveness, exhaled NO, postallergen sputum, symptoms, inhaled β
2-agonist use, or PEF.
In patients with mild-to-moderate atopic asthma, IVL745 did not affect the early and late response to inhaled allergen or markers of airway inflammation, except for a modest reduction in sputum eosinophils.
Riluzole is a novel neuroprotective agent that has been developed for the treatment of amyotrophic lateral sclerosis. A series of studies was undertaken to establish its pharmacokinetics on single- ...and multiple-dose administration in young white male volunteers. The mean absolute oral bioavailability of riluzole (50-mg tablet) was approximately 60%. Maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) values were linearly related to dose for the range studied. Cmax occurred at 1.0 hour to 1.5 hours after administration. Plasma elimination half-life appeared to be independent of dose. After repeated administration of 100 mg riluzole for 10 days, some intraindividual variability in bioavailability was seen. A high-fat meal significantly reduced the rate (tmax = 2 hours compared with 0.8 hours; Cmax = 216 ng.mL-1 compared to 387 ng.mL-1) and extent of absorption (AUC = 1,047 ng.hr.mL-1 versus 1,269 ng.hr.mL-1). With multiple-dose administration, riluzole showed dose-related absorption, although the terminal plasma half-life was prolonged slightly. Steady-state plasma concentrations were achieved within 5 days. Steady-state trough plasma concentrations were significantly higher with a 75-mg dose twice daily than with a 50-mg dose three times daily, although AUC values did not differ.
The pharmacokinetics and tolerability of the novel antiexcitatory agent, riluzole, were compared in 18 healthy elderly and 18 healthy gender- and weight-matched young volunteers. All participants ...received riluzole 50 mg twice daily (the recommended dosage for patients with amyotrophic lateral sclerosis), administered orally for 5 days. The pharmacokinetics of riluzole, determined on the morning of the 5th day of dosing, were not significantly affected by age or gender. The mean terminal elimination half-life (t1/2), however, was statistically significant between elderly and young subjects. Riluzole was well tolerated upon repeat dose administration. Headache was the most frequent adverse event reported, and there was no overt difference in the type, frequency, or severity of adverse events between elderly and young volunteers or between genders. In conclusion, these results indicate that no dosage adjustments of riluzole are required in the elderly.
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. Six parallel groups of 8 healthy men (6 active and 2 placebo/group) were enrolled in the study. Plasma samples were collected for up to 72 hours post-dose. RPR749 and its metabolite RPR772 concentrations were measured by a validated LC/MS/MS method with a minimal quantifiable limit of 1 ng/mL. RPR749 was safe and well tolerated as a single oral dose up to 200 mg. The mean plasma concentrations of RPR749 were approximately 30-fold higher than the mean RPR772 plasma concentrations. The mean terminal half-life (t(1/2)) of RPR749 and RPR772 were similar (approximately 16.4 hours). Mean values for serum insulin, triglycerides, glycerol, and blood glucose remained within normal ranges. Mean FFA concentrations in serum decreased in all treatment groups with the maximal decrease in the 200-mg dose group. In conclusion, RPR749 has the ability to reduce circulating levels of FFA that can be related to plasma RPR749 concentrations and thus possesses pharmacological properties that may be beneficial in treating coronary artery diseases and hyperlipidemia.
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. Hence, if the drug is metabolically stable in the lungs, mass balance and metabolism of inhaled drugs, such as IVL745, can be determined by administering radiolabeled intravenous (IV) and oral drugs and by comparing with the data following Inh administration. The study was a three-period crossover design in 6 healthy subjects to evaluate the absorption, distribution, metabolism, and elimination following IV and oral administration of (14)C-IVL745 (4 mg/50 microCi) and inhaled (10-mg) dose. Serial sampling of blood and excreta was performed maximally up to 168 hours postdose. Plasma IVL745 concentrations were determined using a liquid chromatography tandem mass spectrometry (LC/MS/MS) method with a minimum quantifiable limit of 10 pg/mL. Overall, the drug was safe and well tolerated. The recovery of the radioactive dose varied from 94.8% to 117% for both IV and oral administration. Following IV administration, 90.2% of the radioactive dose was recovered in the feces, suggesting extensive biliary excretion of the drug. After oral administration, 99.7% of the radioactivity was recovered in the feces, and no radioactivity was detected in plasma, suggesting lack of absorption of the drug. Negligible (14)C-radioactivity concentrations were observed in the red blood cell fractions. The mean t(1/2) values were 1.6, 1.5, and 4.4 hours following IV, oral, and Inh administration, respectively. The oral bioavailability of IVL745 was low (< 2%), and the inhaled bioavailability was 26%. The volume of distribution at steady state (V(ss)) was low (19.0 L). The predicted blood clearance of IVL745 was 86 L/h, which was comparable to the commonly used liver blood flow value of 90 L/h. Only a minor fraction of the dose was excreted in the urine with low to moderate renal clearance. The parent drug accounted for 77% to 89% of the dosed radioactivity in excreta. Two major metabolites observed in excreta were mono-o-desmethyl IVL745 and di-o-desmethyl IVL745. The data showed that the drug had negligible oral bioavailability, low oral absorption, 26% inhaled bioavailability, low extent of metabolism, high biliary excretion, and low renal clearance. This knowledge may aid in the prediction of potentially relevant drug-drug interactions and dosing adjustments in high-risk populations for IVL745.
RG 12525 (2-4-2-(1H-tetrazole-5-ylmethyl)phenylmethoxyphenoxymethyl quinolone) is a novel peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist. In vitro microsomal inhibition assays ...indicated that RG 12525 is a potent inhibitor of CYP3A4, with a Ki value of 0.5 microM. With the conservative assumption that the total plasma concentration of drug was available to metabolic enzymes following RG 12525 oral administration, marked inhibition of CYP3A4 was expected to substantially reduce the systemic clearance of compounds metabolized by this enzyme. The possibility also existed for inhibition of intestinal and hepatic CYP3A4 by RG 12525 to reduce "first-pass" metabolism and increase absolute bioavailability of CYP3A4 substrates orally coadministered. Consequently, an in vivo drug-drug interaction study was performed to evaluate the effects of orally administered RG 12525 on in vivo CYP3A4 activity in healthy male subjects. The pharmacokinetics of oral midazolam, a probe for intestinal and hepatic CYP3A activity, was not influenced by either the low (100 mg qd for 4 days) or high (600 mg qd for4 days) RG 12525 dosing regimen despite the resulting total plasma concentrations of inhibitor that were well above in vitro Ki values. The point estimates and 90% confidence intervals for the ratios of mean midazolam AUC for subjects administered 100 mg RG 12525 (110.6; 98.7-124.1) and 600 mg RG 12525 (98.4; 84.4-114.7) versus midazolam alone were within 80% to 125%. To explain these results, factors that could limit the accuracy of in vitro models in predicting metabolic drug interactions, mainly the high degree of RG 12525 protein binding (> 99.9%), were considered. The lack of correlation between the in vitro inhibition of CYP3A4 by RG 12525 and the inconsequential effects of this compound on midazolam pharmacokinetics accentuate the need to recognize factors other than plasma drug concentrations and potency of in vitro enzyme inhibition when extrapolating in vitro data to predict in vivo drug-drug interactions.
PDF
