Kinetics of free and ligand-bound atacicept in human serum.

BAFF (B cell activation factor of the TNF family/B lymphocyte stimulator, BLyS) and APRIL (a proliferation-inducing ligand) are targeted by atacicept, a decoy receptor consisting of the extracellular domain of TACI (transmembrane activator and calcium-modulator and cyclophilin (CAML) interactor) fused to the Fc portion of human IgG1. The purpose of the study was to characterize free and ligand-bound atacicept in humans. Total and active atacicept in serum of healthy volunteers receiving a single dose of subcutaneous atacicept or in patients treated weekly for one year were measured by ELISA, Western blot, or cell-based assays. Pharmacokinetics of free and bound atacicept were predicted based on total atacicept ELISA results. Persistence of complexes of purified atacicept bound to recombinant ligands was also monitored in mice. Results show that unbound or active atacicept in human serum exceeded 0.1 µg/ml for one week post administration, or throughout a 1-year treatment with weekly administrations. After a single administration of atacicept, endogenous BAFF bound to atacicept was detected after 8 h then increased about 100-fold within 2 to 4 weeks. Endogenous heteromers of BAFF and APRIL bound to atacicept also accumulated, but atacicept-APRIL complexes were not detected. In mice receiving intravenous injections of purified complexes pre-formed in vitro, atacicept-BAFF persisted longer (more than a week) than atacicept-APRIL (less than a day). Thus, only biologically inactive BAFF and BAFF-APRIL heteromers accumulate on atacicept in vivo. The measure of active atacicept provides further support for the once-weekly dosing regimen implemented in the clinical development of atacicept

One slope or two? Detecting statistically significant breaks of slope in geophysical data, with application to fracture scaling relationships

The scaling of displacement as a function of length is important for a variety of applications which depend on the mechanical and hydraulic properties of faults and fractures. Recently it has been suggested that the power-law exponent nu which has been found to characterise this relationship may change significantly at a characteristic length for a variety of reasons, for example when cracks begin to interact, or when faults grow to a length comparable to a characteristic size in the brittle layer. Such a break of slope requires a second straight line, requiring two extra model parameters. Here we present a new method for analysing such data, which penalises the extra parameters using a modified form of Schwarz's Information Criterion, and a Bayesian approach which represents uncertainty in the unknown parameters. We apply the method to data from the Krafla fissure zone in the north of Iceland, and find a significant break of slope, from nu approximate to 3/2 to nu approximate to 2/3, at a characteristic length of 12 m

ps7 133 exposure response modelling and exposure safety modelling analyses in two phase ii studies of atacicept in sle

Purpose Atacicept targets the B-cell stimulating factors BLyS and APRIL, and has been shown to reduce SLE disease activity. Methods APRIL-SLE (NCT00624338) and ADDRESS II (NCT01972568) were phase II, multicenter studies in patients (pts) with autoantibody-positive SLE randomised (1:1:1) to weekly SC injections of atacicept (75 or 150 mg) or placebo (PBO). In APRIL-SLE, pts had BILAG A/B flare at Screening that was reduced to BILAG C/D before randomization using corticosteroids; the primary endpoint was BILAG A/B flare over 52 weeks. In ADDRESS II, pts had SLEDAI-2K≥6 at Screening; the primary endpoint was SRI-4 response at Week 24. SLE responder index (SRI)−6 response was analysed post-hoc in high disease activity (HDA; SLEDAI-2K≥10) pts. Population pharmacokinetic (PK) model-derived exposure vs the probability of response (BILAG A/B flare, SRI-4, SRI-6), exploratory analysis of exposure vs safety, and population model simulations of serum IgG were analysed. Results Exposure-response modelling suggests a relationship between atacicept exposure and SLE clinical response [figure 1], including serum IgG changes from baseline. The optimal atacicept exposure was AUCtau,ss ≥~1 mg.hr/mL, which is more achievable with weekly SC doses of atacicept 150 mg than 75 mg across a range of body weights. Body weight-based dosing is unlikely to offer any value over a fixed 150 mg dose, based on comparable predicted clinical response. In HDA pts, greater reductions in serum IgG from baseline corresponded to a higher probability of SRI-6 response. Greater IgG reductions from baseline were associated with higher atacicept exposure; however, even at the highest exposure range, mean IgG reductions did not exceed ~40%. There was no association between serious/severe infections and exposure by PK quartile. Conclusions Exposure-response modelling indicated robust relationships between atacicept exposure and clinical response or IgG levels, supporting the proposed mechanism of action for atacicept. Atacicept 150 mg weekly SC is likely to provide an effective level of exposure with an acceptable safety profile. There was no evidence of an increased risk of severe or serious infections at higher exposures. Based on these results, the 150 mg dose merits further evaluation

Effect of faults and fractures on oilfield flow rate data

see Abstract Volum

Effect of faults and fractures on oilfield flow rate data

see Abstract VolumeIstituto Nazionale di Geofisica e Vulcanologia, Italy (INGV) Centre National de la Recherche Scientifique (CNRS) ExxonMobil Upstream Research CompanyUnpublishedErice, italyope

Statistical Reservoir Model: calibrating faults and fractures, and predicting reservoir response to water flood

Abstract: This paper describes the new concept of a ‘Statistical Reservoir Model ’ to determine significant well-pair correlations. We solve this conceptual problem using a predictive error filter, combined with Bayesian methods that identify those well pairs that are related to each other with statistical significance, for the Gullfaks reservoir in the North Sea. Significant, long-range, corre-lations in the whole field are found at an optimal time lag of one month. The correlation function for significantly-correlated well pairs, after normalization for the distribution of available wells, shows a long-range power-law decay that is consistent with a critical-point response at the reser-voir scale. A principal component analysis shows a strong correlation with the location and orien-tation of faults that intersect the main producing horizon. A predictive experiment shows that the model performs very well both in history matching and predictive mode on a time scale of about one month. Hydrocarbon reservoirs comprise subsurface bodies of rock of suitable porosity and permeability to allow the storage and transmittal of oil and gas. Producer wells are sunk into a reservoir to allo