A randomized, phase II study of sequential belimumab and rituximab in primary Sjögren's syndrome

BACKGROUND: Primary Sjögren’s syndrome (pSS) is characterized by B cell hyperactivity and elevated B-lymphocyte stimulator (BLyS). Anti-BLyS treatment (e.g., belimumab) increases peripheral memory B cells; decreases naive, activated, and plasma B cell subsets; and increases stringency on B cell selection during reconstitution. Anti-CD20 therapeutics (e.g., rituximab) bind and deplete CD20-expressing B cells in circulation but are less effective in depleting tissue-resident CD20(+) B cells. Combined, these 2 mechanisms may achieve synergistic effects. METHODS: This 68-week, phase II, double-blind study (GSK study 201842) randomized 86 adult patients with active pSS to 1 of 4 arms: placebo, s.c. belimumab, i.v. rituximab, or sequential belimumab + rituximab. RESULTS: Overall, 60 patients completed treatment and follow-up until week 68. The incidence of adverse events (AEs) and drug-related AEs was similar across groups. Infections/infestations were the most common AEs, and no serious infections of special interest occurred. Near-complete depletion of minor salivary gland CD20(+) B cells and a greater and more sustained depletion of peripheral CD19(+) B cells were observed with belimumab + rituximab versus monotherapies. With belimumab + rituximab, reconstitution of peripheral B cells occurred, but it was delayed compared with rituximab. At week 68, mean (± standard error) total EULAR Sjögren’s syndrome disease activity index scores decreased from 11.0 (1.17) at baseline to 5.0 (1.27) for belimumab + rituximab and 10.4 (1.36) to 8.6 (1.57) for placebo. CONCLUSION: The safety profile of belimumab + rituximab in pSS was consistent with the monotherapies. Belimumab + rituximab induced enhanced salivary gland B cell depletion relative to the monotherapies, potentially leading to improved clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02631538. FUNDING: Funding was provided by GSK

Quantifying disease activity in rheumatoid arthritis with the TSPO PET ligand 18 F-GE-180 and comparison with 18 F-FDG and DCE-MRI

Abstract: Purpose: While the aetiology of rheumatoid arthritis (RA) remains unclear, many of the inflammatory components are well characterised. For diagnosis and therapy evaluation, in vivo insight into these processes would be valuable. Various imaging probes have shown value including dynamic contrast-enhanced (DCE) MRI and PET/CT using 18F-fluorodeoxyglucose (18F-FDG) or tracers targeting the translocator protein (TSPO). To evaluate 18F-GE-180, a novel TSPO PET tracer, for detecting and quantifying disease activity in RA, we compared 18F-GE-180 uptake with that of 18F-FDG and DCE-MRI measures of inflammation. Methods: Eight RA patients with moderate-to-high, stable disease activity and active disease in at least one wrist were included in this study (NCT02350426). Participants underwent PET/CT examinations with 18F-GE-180 and 18F-FDG on separate visits, covering the shoulders and from the pelvis to the feet, including hands and wrists. DCE-MRI was performed on one affected hand. Uptake was compared visually between tracers as judged by an experienced radiologist and quantitatively using the maximum standardised uptake value (SUVmax). Uptake for both tracers was correlated with DCE-MRI parameters of inflammation, including the volume transfer coefficient Ktrans using Pearson correlation (r). Results: PET/CT imaging with 18F-GE-180 in RA patients showed marked extra-synovial uptake around the affected joints. Overall sensitivity for detecting clinically affected joints was low (14%). 18F-GE-180 uptake did not or only weakly correlate with DCE-MRI parameters in the wrist (r = 0.09–0.31). 18F-FDG showed higher sensitivity for detecting symptomatic joints (34%), as well as strong positive correlation with DCE-MRI parameters (SUVmax vs. Ktrans: r = 0.92 for wrist; r = 0.68 for metacarpophalangeal joints). Conclusions: The correlations between DCE-MRI parameters and 18F-FDG uptake support use of this PET tracer for quantification of inflammatory burden in RA. The TSPO tracer 18F-GE-180, however, has shown limited use for the investigation of RA due to its poor sensitivity and ability to quantify disease activity in RA

First Administration of the Fc-Attenuated Anti-beta Amyloid Antibody GSK933776 to Patients with Mild Alzheimer's Disease: A Randomized, Placebo-Controlled Study

Objectiv

A Study to Investigate the Efficacy and Safety of an Anti-Interleukin-18 Monoclonal Antibody in the Treatment of Type 2 Diabetes Mellitus.

Clinical Trial, Phase II; Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov't;OBJECTIVE Evidence suggests that chronic subclinical inflammation plays an important role in the pathogenesis of type 2 diabetes (T2DM). Circulating levels of interleukin (IL)-18 appear to be associated with a number of micro- and macrovascular comorbidities of obesity and T2DM. This study was designed to investigate whether inhibition of IL-18 had any therapeutic benefit in the treatment of T2DM. Preliminary efficacy, safety and tolerability, pharmacokinetics, and pharmacodynamics of the anti-IL-18 monoclonal antibody, GSK1070806, were assessed. RESEARCH DESIGN AND METHODS This was a multicentre, randomized, single-blind (sponsor-unblinded), placebo-controlled, parallel-group, phase IIa trial. Obese patients of either sex, aged 18-70 years, with poorly controlled T2DM on metformin monotherapy were recruited. Patients received two doses, of placebo (n = 12), GSK1070806 0.25 mg/kg (n = 13) or GSK1070806 5 mg/kg (n = 12). The primary end-point was the change from baseline in fasting plasma glucose and weighted mean glucose area under the curve (AUC)(0-4 hours) postmixed meal test on Days 29, 57, and 85. RESULTS Thirty-seven patients were randomized to one of the three treatment arms. There were no statistically significant effects of GSK1070806 doses on fasting plasma glucose levels, or weighted mean glucose AUC(0-4 hours) compared with placebo. CONCLUSIONS GSK1070806 was well tolerated, and inhibition of IL-18 did not lead to any improvements in glucose control. However, because of study limitations, smaller, potentially clinically meaningful effects of IL-18 inhibition cannot be excluded. TRIAL REGISTRATION ClinicalTrials.gov NCT01648153.Support was provided by GlaxoSmithKline.Ye

Inhibition of TNF-α induced cytotoxicity in a mouse L929 cell-based assay.

<p>DMS5540 (green), DOM1m-21-23 (blue) and mouse TNFR2-Fc (red) were titrated over a 1000-fold concentration range to determine their ability to inhibit mouse TNF-α (20 pg/ml) induced cytotoxicity in L929 cells. Sample concentration is plotted versus % inhibition of cytotoxicity.</p

DMS5540 PD determined by protection provided to IL-6 serum increases after <i>in vivo</i> TNF-α challenge.

<p>Eight mice per dose group were injected with DMS5540, DMS5538 (Dummy control) or nothing at the indicated dose in mg/kg. Four hours later all mice indicated received a bolus injection of mouse TNF-α (100 ng/mouse) and 2 hours later serum samples were taken to determine IL-6 levels. (A) Boxplot for IL-6 serum level (pg/ml) for each dose group. Boxplot description: the horizontal line is the median and the diamond is the mean. The upper and lower ends of the box are located at the upper quartile (Q3) and lower quartile (Q1) respectively. The whiskers show the minimum observation before 1.5 x IQR below the box and the maximum observation before 1.5 x IQR above the box. Observations beyond the error bars are shown as individual data points. (B) Individual mouse IL-6 serum levels (pg/ml) for all 8 mice in each dose group.</p

Model Adjusted Mean (95% CI) Change from Baseline Plot for Fasting Plasma Glucose (mmol/l) (All Visits up to Day 85) [Per Protocol Population].

<p>Model Adjusted Mean (95% CI) Change from Baseline Plot for Fasting Plasma Glucose (mmol/l) (All Visits up to Day 85) [Per Protocol Population].</p

PK parameters following dosing with DMS5540 as determined by WinNonLin analysis.

<p>Abbreviations: T1/2: terminal half-life of DMS5540; Tmax: Time at which maximum concentration is reached; Mean Cmax: mean maximum concentration across 3 mice; SE of Cmax: Standard Error of Cmax; AUC: Area Under the concentration/time Curve extrapolated to infinity; Vz: volume of distribution over terminal phase; Cl: Clearance; MRT: Mean Residence Time.</p><p>PK parameters following dosing with DMS5540 as determined by WinNonLin analysis.</p

Baseline Demographics.

<p>Baseline Demographics.</p

Characterisation of DMS5540 purity and binding properties.

<p>(A) Protein sequence of DMS5540: αTNFR1 Vh dAb (blue), short AST linker (black) and Vk AlbudAb (red). (B) SDS-PAGE analysis: 10μg of affinity purified DMS5540 under non-reducing conditions compared with Novex Sharp pre-stained protein markers (Invitrogen). (C) Size exclusion chromatography analysis: Injection (10μl) of 0.6mg/ml DMS5540 onto TSK G2000 SW_XL column at 0.5ml/min: main peak at 18.1min (95.5%) that of monomeric DMS5540, with small (<5%) amount of DMS5540 dimer present at 16.4min. Surface plasmon resonance analysis of DMS5540 binding to mouse (D) and human TNFR1 (E). The dissociation equilibrium constants for DMS5540 binding to mouse and human TNFR1 were determined using a Biacore T100. Constants were calculated by injecting DMS5540 over 2-fold dilutions from 16 nM to 0.125 nM over a mouse TNFR1 or human TNFR1 coated chip surface.</p