Gain-of-function mutations in a serine protease, proprotein convertase subtilisin/kexin 9 (PCSK9), have been associated with high plasma levels of low-density lipoprotein (LDL) cholesterol and an increased incidence of coronary heart disease. Previous studies showed that PCSK9 loss-of-function mutations in patients were associated with low levels of LDL cholesterol and a reduced incidence of coronary heart disease. This suggested that pharmacologic inhibition of PCSK9 could lower LDL cholesterol levels in patients with hypercholesterolemia. REGN727/SAR236553 (REGN727) is an investigational, fully human monoclonal antibody highly specific for human PCSK9. This antibody blocks the interaction of PCSK9 with LDL receptors.This report presents the results of 3 phase 1 studies of REGN727 in humans. The participants were healthy volunteers and patients with familial or nonfamilial hypercholesterolemia. Three separate clinical studies of REGN727 were conducted. The first two compared the effect of single doses of REGN727, administered either intravenously (n = 40) or subcutaneously (n = 32), in healthy volunteers and a placebo. After these 2 single-dose studies, a randomized, placebocontrolled multiple-dose trial that investigated the effect of REGN727in 3 separate cohorts with hypercholesterolemia was conducted. The first cohort was composed of 21 subjects with heterozygous familial hypercholesterolemia and the second cohort consisted of 30 subjects with nonfamilial hypercholesterolemia. All patients in these 2 cohorts were receiving atorvastatin therapy and had a baseline LDL cholesterol level greater than 100 mg/dL (2.6 mM). The third cohort was composed of 10 subjects with nonfamilial hypercholesterolemia who had a baseline LDL cholesterol level greater than 130 mg/dL (3.4 mM); these patients were treated only with a modified diet.Patients in the multiple-dose study were randomly assigned to receive subcutaneous REGN727 (50, 100, or 150 mg) or placebo administered on days 1, 29, and 43. The primary study outcome was the incidence of adverse events. The major secondary end point evaluated was the effect of REGN727 on the lipid profile.None of the subjects receiving REGN727 withdrew from the study early because of an adverse event. There was a significant reduction in levels of LDL cholesterol among patients receiving REGN727 in all studies. Levels of LDL in the multiple-dose study were as follows: REGN727 doses of 50, 100, and 150 mg reduced LDL levels in the combined atorvastatin-treated populations to 77.5 mg/dL (2.00 mL), 61.3 mg/dL (1.59 mL), and 53.8 mg/dL (1.39 mL), respectively; differences in the change from baseline with the 50-, 100-, and 150-mg doses were j39.2, j53.7, and j61.0 percentage points compared with placebo (P G 0.001 for all 3 comparisons).These phase 1 trials suggest a role for PCSK9 in the regulation of LDL cholesterol in humans.
Adults with moderate to severe AD report multidimensional burden including disease activity, patient-reported symptoms, comorbidities, and quality-of-life impact.
In three phase 1 trials, a monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels in healthy volunteers and in subjects with familial or nonfamilial hypercholesterolemia. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT01026597, NCT01074372, and NCT01161082.).
Background:Recent studies suggest that blockade of the NLRP3 (cryopyrin) inflammasome interleukin 1β (IL1β) pathway may offer a new treatment strategy for gout.Objective:To explore the potential utility of rilonacept (IL1 Trap) in patients with chronic active gouty arthritis in a proof-of-concept study.Methods:This 14-week, multicentre, non-randomised, single-blind, monosequence crossover study of 10 patients with chronic active gouty arthritis included a placebo run-in (2 weeks), active rilonacept treatment (6 weeks) and a 6-week post-treatment follow-up.Results:Rilonacept was generally well tolerated. No deaths and no serious adverse events occurred during the study. One patient withdrew owing to an injection-site reaction. Patients’ self-reported median pain visual analogue scale scores significantly decreased from week 2 (after the placebo run-in) to week 4 (2 weeks of rilonacept) (5.0 to 2.8; p<0.049), with sustained improvement at week 8 (1.3; p<0.049); 5 of 10 patients reported at least a 75% improvement. Median symptom-adjusted and severity-adjusted joint scores were significantly decreased. High-sensitivity C-reactive protein levels fell significantly.Conclusions:This proof-of-concept study demonstrated that rilonacept is generally well tolerated and may offer therapeutic benefit in reducing pain in patients with chronic refractory gouty arthritis, supporting the need for larger, randomised, controlled studies of IL1 antagonism such as with rilonacept for this clinical indication.
In laboratory experiments, infants are sensitive to patterns of visual features that co-occur (e.g., Fiser & Aslin, 2002). Once infants learn the statistical regularities, however, what do they do with that knowledge? Moreover, which patterns do infants learn in the cluttered world outside of the laboratory? Across 4 experiments, we show that 9-month-olds use this sensitivity to make inferences about object properties. In Experiment 1, 9-month-old infants expected co-occurring visual features to remain fused (i.e., infants looked longer when co-occurring features split apart than when they stayed together). Forming such expectations can help identify integral object parts for object individuation, recognition, and categorization. In Experiment 2, we increased the task difficulty by presenting the test stimuli simultaneously with a different spatial layout from the familiarization trials to provide a more ecologically valid condition. Infants did not make similar inferences in this more distracting test condition. However, Experiment 3 showed that a social cue did allow inferences in this more difficult test condition, and Experiment 4 showed that social cues helped infants choose patterns among distractor patterns during learning as well as during test. These findings suggest that infants can use feature co-occurrence to learn about objects and that social cues shape such foundational learning in distraction-filled environments.
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