Long-term Efficacy and Tolerability of RPC4046 in an Open-Label Extension Trial of Patients With Eosinophilic Esophagitis.

BACKGROUND & AIMS: The short-term efficacy of RPC4046, a monoclonal antibody against interleukin-13, has been shown in patients with eosinophilic esophagitis (EoE). We investigated the long-term efficacy and safety of RPC4046 in an open-label, long-term extension (LTE) study in adults with EoE. METHODS: We analyzed data from 66 patients who completed the 16-week, double-blind, induction portion of a phase 2 study of RPC4046 (180 mg or 360 mg/wk) vs placebo and then completed a 52-week LTE, receiving open-label RPC4046 360 mg/wk. The study was conducted at 28 centers in 3 countries; patients were enrolled between September 2014 and January 2017. Outcomes were stratified by double-blind dose group and included esophageal eosinophil counts, EoE endoscopic reference score, EoE histologic scoring system score, symptom-based EoE activity index score, and safety. RESULTS: By week 12 of the LTE, esophageal eosinophil mean and peak counts, total EoE endoscopic reference scores, and EoE histologic scoring system grade and stage scores did not differ considerably between patients who originally received placebo vs RPC4046. Most patients maintained responses through week 52. Symptom remission (symptom-based EoE activity index score, ≤20) increased from 14% at LTE entry to 67% at LTE week 52 in placebo‒RPC4046 patients and from 30% to 54% in RPC4046‒RPC4046 (either dose) patients. Of the 28 patients who did not have a histologic response to RPC4046 during the double-blind induction phase, 10 patients (36%) achieved response during the LTE. The most common adverse events were upper respiratory tract infection (21%) and nasopharyngitis (14%). CONCLUSIONS: One year of treatment with RPC4046 is generally well tolerated and results in continued improvement and/or maintenance of endoscopic, histologic, and clinical measures of EoE disease activity relative to baseline. TRIAL REGISTRATION: NCT02098473.

RPC4046, a Monoclonal Antibody Against IL13, Reduces Histologic and Endoscopic Activity in Patients With Eosinophilic Esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is a chronic, esophageal, type 2 inflammatory response associated with increased serum levels of interleukin 13 (IL13), which might contribute to its pathogenesis. RPC4046, a recombinant humanized monoclonal antibody against IL13, prevents its binding to the receptor subunits IL13RA1 and IL13RA2. We performed a phase 2 trial to evaluate the efficacy and safety of RPC4046 in patients with EoE. METHODS: We performed a multicenter, double-blind trial of 99 adults with active EoE randomly assigned (1:1:1) to groups given RPC4046 (180 or 360 mg) or placebo once weekly for 16 weeks, from September 2014 through December 2015. Patients were seen at day 1 (baseline) and weeks 2, 4, 8, 12, and 16. They underwent esophagogastroduodenoscopy and biopsies were collected at baseline and week 16. Patients completed a daily dysphagia symptom diary through week 16 and patient-reported outcome data were collected. The primary outcome was change in mean esophageal eosinophil count in the 5 high-power fields (hpfs) with the highest level of inflammation. RESULTS: At week 16, mean changes in esophageal eosinophil count per hpf were a reduction of 94.8 ± 67.3 in patients who received 180 mg RPC4046 (P < .0001) and a reduction of 99.9 ± 79.5 in patients who received 360 mg RPC4046 (P < .0001) compared with a reduction of 4.4 ± 59.9 in patients who received placebo. The 360-mg RPC4046 group, compared with the placebo group, showed significant reductions in validated endoscopic severity score at all esophageal locations (P < .0001), validated histologic grade and stage scores (both P < .0001), and clinician's global assessment of disease severity (P = .0352); they had a numerical reduction in scores from the dysphagia symptom diary (P = .0733). Significant reductions in esophageal eosinophil counts and histologic and endoscopic features were observed in patients with steroid-refractory EoE who received RPC4046. The most common adverse events were headache and upper respiratory tract infection. CONCLUSIONS: In a phase 2 trial of patients with EoE, we found RPC4046 (a monoclonal antibody against IL13) to reduce histologic and endoscopic features compared with placebo. RPC4046 was well tolerated. ClinicalTrials.gov no: NCT02098473.

Modeling orbital gamma-ray spectroscopy experiments at carbonaceous asteroids.

To evaluate the feasibility of measuring differences in bulk composition among carbonaceous meteorite parent bodies from an asteroid or comet orbiter, we present the results of a performance simulation of an orbital gamma-ray spectroscopy (GRS) experiment in a Dawn-like orbit around spherical model asteroids with a range of carbonaceous compositions. The orbital altitude was held equal to the asteroid radius for 4.5 months. Both the asteroid gamma-ray spectrum and the spacecraft background flux were calculated using the MCNPX Monte-Carlo code. GRS is sensitive to depths below the optical surface (to ≈20-50 cm depth depending on material density). This technique can therefore measure underlying compositions beneath a sulfur-depleted (e.g., Nittler et al. 2001) or desiccated surface layer. We find that 3σ uncertainties of under 1 wt% are achievable for H, C, O, Si, S, Fe, and Cl for five carbonaceous meteorite compositions using the heritage Mars Odyssey GRS design in a spacecraft-deck-mounted configuration at the Odyssey end-of-mission energy resolution, FWHM = 5.7 keV at 1332 keV. The calculated compositional uncertainties are smaller than the compositional differences between carbonaceous chondrite subclasses.

Hydrogen and major element concentrations on 433 Eros: Evidence for an L- or LL-chondrite-like surface composition.

A reanalysis of NEAR X-ray/gamma-ray spectrometer (XGRS) data provides robust evidence that the elemental composition of the near-Earth asteroid 433 Eros is consistent with the L and LL ordinary chondrites. These results facilitated the use of the gamma-ray measurements to produce the first in situ measurement of hydrogen concentrations on an asteroid. The measured value, 1100-700+1600 ppm, is consistent with hydrogen concentrations measured in L and LL chondrite meteorite falls. Gamma-ray derived abundances of hydrogen and potassium show no evidence for depletion of volatiles relative to ordinary chondrites, suggesting that the sulfur depletion observed in X-ray data is a surficial effect, consistent with a space-weathering origin. The newfound agreement between the X-ray, gamma-ray, and spectral data suggests that the NEAR landing site, a ponded regolith deposit, has an elemental composition that is indistinguishable from the mean surface. This observation argues against a pond formation process that segregates metals from silicates, and instead suggests that the differences observed in reflectance spectra between the ponds and bulk Eros are due to grain size differences resulting from granular sorting of ponded material.

The major-element composition of Mercury's surface from MESSENGER X-ray spectrometry.

X-ray fluorescence spectra obtained by the MESSENGER spacecraft orbiting Mercury indicate that the planet's surface differs in composition from those of other terrestrial planets. Relatively high Mg/Si and low Al/Si and Ca/Si ratios rule out a lunarlike feldspar-rich crust. The sulfur abundance is at least 10 times higher than that of the silicate portion of Earth or the Moon, and this observation, together with a low surface Fe abundance, supports the view that Mercury formed from highly reduced precursor materials, perhaps akin to enstatite chondrite meteorites or anhydrous cometary dust particles. Low Fe and Ti abundances do not support the proposal that opaque oxides of these elements contribute substantially to Mercury's low and variable surface reflectance.

Radioactive elements on Mercury's surface from MESSENGER: implications for the planet's formation and evolution.

The MESSENGER Gamma-Ray Spectrometer measured the average surface abundances of the radioactive elements potassium (K, 1150 ± 220 parts per million), thorium (Th, 220 ± 60 parts per billion), and uranium (U, 90 ± 20 parts per billion) in Mercury's northern hemisphere. The abundance of the moderately volatile element K, relative to Th and U, is inconsistent with physical models for the formation of Mercury requiring extreme heating of the planet or its precursor materials, and supports formation from volatile-containing material comparable to chondritic meteorites. Abundances of K, Th, and U indicate that internal heat production has declined substantially since Mercury's formation, consistent with widespread volcanism shortly after the end of late heavy bombardment 3.8 billion years ago and limited, isolated volcanic activity since.

Medical status of school-age children reentering foster care.

Medical status changes between foster care placements were investigated to determine whether medical status improves and whether medical status changes predict reentry into care. Three hundred and ninety-two school-age children reentering foster care received comprehensive medical evaluation on each foster care entry. Results indicated that students reentering care had worsened medical status. Comparison with matched students having a single foster care placement did not show medical status predictive of foster care reentry but suggested that some medical status declines were age related.

The need for educational assessment of children entering foster care.

Comprehensive medical and mental health evaluations of children in foster care are recommended within 30 days of entering care. What constitutes a comprehensive evaluation has yet to be established. This study examines the need to include educational assessment as a component of the comprehensive evaluation. Rates of achievement and language problems for Arkansas school-age children are compared with rates of medical and psychiatric disorders to assess the relative need for including educational assessment.

A comparison of shear bond strengths of orthodontic brackets using various light sources, light guides, and cure times.

The objective of this study was to evaluate the effects of different cure times, light sources, and light guides on shear bond strength of orthodontic brackets bonded with Transbond XT (3M Unitek, Monrovia, Calif) to bovine enamel. Specifically, the Power Slot (Reliance Orthodontic Products, Itasca, Ill) light guide was placed on 4 visible light sources to compare shear bond strengths and recommended cure times with the light guides provided with each light source. We randomly divided 240 bovine mandibular incisors into 16 groups; each group consisted of 15 teeth mounted in an acrylic block. Each group of teeth was polymerized with a specific light and light guide combination. Eight groups were sheared after 5 minutes and the remaining 8 groups after 24 hours. After bonding, all brackets were subjected to a shear force with a testing machine. Overall, there was a significant increase in bond strengths of the 24-hour groups compared with the 5-minute shearing groups. However, there were no statistical differences (P =.05) within the 24-hour test groups or the 5-minute test groups. The results of this study indicate that, compared with standard light guides, the Power Slot and the Turbo Tip (Ormco Sybron Dental Specialties, Orange, Calif) light guides can significantly reduce the curing times (10 seconds per bracket; 5 seconds each from mesial and distal) without affecting their shear bond strengths. Therefore, the Power Slot and the Turbo Tip light guides with their collimation of visible light to increase its intensity can be recommended as advantageous alternatives for curing composite resins for orthodontic bonding procedures.