Early effects of tocilizumab in the treatment of moderate to severe active rheumatoid arthritis: a one-week sub-study of a randomised controlled trial (Rapid Onset and Systemic Efficacy [ROSE] Study).

OBJECTIVES: Tocilizumab has demonstrated efficacy in managing rheumatoid arthritis (RA) from week 2 onward. This sub-study assessed effects of tocilizumab plus disease-modifying anti-rheumatic drugs (DMARDs) during the first week of therapy. METHODS: Rapid Onset and Systemic Efficacy was a 24-week, randomised, double-blind, placebo-controlled, parallel-group trial. Adults with moderate to severe active RA taking DMARDs received tocilizumab 8 mg/kg (or placebo) plus DMARDs every 4 weeks. Data were analysed from the first 62 patients at designated study sites who agreed to clinical evaluation and blood sampling at days 3 and 7 and had C-reactive protein levels ≥1 mg/dl. Outcomes included American College of Rheumatology core data set measures, disease activity score using 28 joints (DAS28) and routine assessment of patient index data 3 (RAPID3) scores. RESULTS: Baseline evaluations were similar between groups (tocilizumab, n=40; placebo, n=22). Patient global assessments of disease activity and pain improved significantly in favour of tocilizumab (mean change from baseline to day 7: -16.2 [tocilizumab], 0.8 [placebo] [p=0.005] and -12.2 [tocilizumab], 1.4 [placebo] [p=0.01], respectively). Physician global assessment of disease activity also improved more with tocilizumab (-15.4 [tocilizumab], -5.6 [placebo] [p=0.05]). Changes from baseline in tender/swollen joint counts, physical function and RAPID3 scores were not significantly different between groups. DAS28 significantly improved with tocilizumab versus placebo at day 7 (-1.16 [tocilizumab], -0.27 [placebo] [p=0.007]). CONCLUSIONS: Tocilizumab showed significant improvement in patient-reported disease activity, pain and DAS28 score as early as day 7 after first infusion, earlier than physician-reported measures, which may take longer to manifest.

Population Pharmacokinetic Modeling of Lucitanib in Patients with Advanced Cancer.

BACKGROUND: Lucitanib is an oral, potent, selective inhibitor of the tyrosine kinase activity of vascular endothelial growth factor receptors 1‒3, fibroblast growth factor receptors 1‒3, and platelet-derived growth factor receptors alpha/beta. OBJECTIVE: We aimed to develop a population pharmacokinetics (PopPK) model for lucitanib in patients with advanced cancers. METHODS: PopPK analyses were based on intensive and sparse oral pharmacokinetic data from 5 phase 1/2 clinical studies of lucitanib in a total of 403 patients with advanced cancers. Lucitanib was administered at 5‒30 mg daily doses as 1 of 2 immediate-release oral formulations: a film-coated tablet or a hard gelatin capsule. RESULTS: Lucitanib pharmacokinetics were best described by a 2-compartment model with zero-order release into the dosing compartment, followed by first-order absorption and first-order elimination. Large between-subject pharmacokinetic variability was partially explained by body weight. No effects of demographics or tumor type on lucitanib pharmacokinetics were observed. The model suggested that the formulation impacted release duration (tablet, 0.243 h; capsule, 0.814 h), but the effect was not considered clinically meaningful. No statistically significant effects were detected for concomitant cytochrome P450 (CYP) 3A4 inhibitors or inducers, CYP2C8 or P-glycoprotein inhibitors, serum albumin, mild/moderate renal impairment, or mild hepatic impairment. Concomitant proton pump inhibitors had no clinically significant effect on lucitanib absorption. CONCLUSIONS: The PopPK model adequately described lucitanib pharmacokinetics. High between-subject pharmacokinetic variability supports a safety-based dose-titration strategy currently being used in an ongoing clinical study of lucitanib to optimize drug exposure and clinical benefit. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01283945, NCT02053636, ISRCTN23201971, NCT02202746, NCT02109016.

The G protein-coupled receptor S1P2 regulates Rho/Rho kinase pathway to inhibit tumor cell migration.

Sphingosine 1-phosphate (S1P) is a lysophospholipid that exerts a variety of responses in cells such as proliferation, migration, and survival. These effects are mediated by G protein-coupled receptors on the cell surface (S1P1-5), which activate downstream signaling intermediates such as Rac and Rho GTPases. Mechanisms of S1P action in human glioblastoma cells are not well defined. S1P receptors (1-5) and S1P-metabolizing enzymes were expressed in three human glioblastoma cell lines. S1P had a profound and differential effect on glioblastoma cell migration. U87 cells treated with S1P showed a significant increase in migration, whereas U118 and U138 cell lines were strongly inhibited. S1P-mediated inhibition correlated with S1P2 receptor expression. FTY720-P, an S1P analogue that binds all S1P receptors except S1P2, did not inhibit glioblastoma cell migration. Overexpression of S1P2 further suppressed migration, and blockage of S1P2 mRNA expression by small interfering RNA reversed the inhibitory effect. Contrary to previous reports showing bimodal regulation of Rac activity and migration by S1P2 receptor stimulation, both Rac1 and RhoA GTPases were activated by S1P treatment in native cells and cells overexpressing S1P2. Treatment of U118 cells with the Rho-associated protein kinase (ROCK) inhibitor Y-27632 restored migration suggesting that ROCK-dependent mechanisms are important. Actin staining of S1P stimulated U118 cells overexpressing beta-galactosidase resulted in pronounced stress fiber formation that was exacerbated by S1P2 overexpression, partially blocked by S1P1, or totally abolished by pretreatment with Y-27632. These data provide evidence of a novel mechanism of S1P inhibition of tumor cell migration via Rho kinase-dependent pathway.

Tocilizumab as monotherapy or in combination with nonbiologic disease-modifying antirheumatic drugs: twenty-four-week results of an open-label, clinical practice study.

OBJECTIVE: To assess the safety and tolerability of tocilizumab (TCZ) as monotherapy or in combination with nonbiologic disease-modifying antirheumatic drugs (DMARDs) in patients with moderate to severe rheumatoid arthritis (RA) who had an inadequate response at study entry to their current treatment with biologic agents or DMARDs. METHODS: This 24-week, multicenter, open-label, phase IIIb study conducted in the US enrolled 886 patients. Treatments were allocated to patients based on their current therapy at study entry. Patients receiving monotherapy with biologic agents were assigned to TCZ 8 mg/kg monotherapy. All other patients were randomized to either TCZ 4 mg/kg + DMARDs or TCZ 8 mg/kg + DMARDs. The primary end point was the number and percentage of patients with serious adverse events (SAEs) during 24 weeks of TCZ treatment. Efficacy assessments were evaluated as secondary outcomes. Data were analyzed descriptively. RESULTS: Overall, 69 patients (7.8%) reported ≥1 SAEs. The rate of SAEs per 100 person-years was 28.3 (95% confidence interval [95% CI] 23.1-34.4) overall and was similar across treatment groups: 29.1 (95% CI 21.0-39.2), 30.3 (95% CI 22.2-40.2), and 20.6 (95% CI 10.3-36.9) in the TCZ 4/8 mg/kg + DMARDs, TCZ 8 mg/kg + DMARDs, and TCZ 8 mg/kg monotherapy groups, respectively. The most common SAEs were infections (i.e., pneumonia [1.0%] and cellulitis [0.9%]). In addition, American College of Rheumatology response rates and reductions in mean Disease Activity Score based on a 28-joint count were generally similar among treatment groups. CONCLUSION: The safety findings in this study were consistent with the previously identified safety profile of TCZ. TCZ had an AE profile consistent with prior randomized blinded studies and was effective when administered as either monotherapy or in combination with DMARDs for the treatment of RA.

The human EMAP-like protein-70 (ELP70) is a microtubule destabilizer that localizes to the mitotic apparatus.

In this report, we show that the echinoderm microtubule (MT)-associated protein (EMAP) and related EMAP-like proteins (ELPs) share a similar domain organization with a highly conserved hydrophobic ELP (HELP) domain and a large tryptophan-aspartic acid (WD) repeat domain. To determine the function of mammalian ELPs, we generated antibodies against a 70-kDa human ELP and showed that ELP70 coassembled with MTs in HeLa cell extracts and colocalized with MTs in the mitotic apparatus. To determine whether ELP70 bound to MTs directly, human ELP70 was expressed and purified to homogeneity from baculovirus-infected Sf9 cells. Purified ELP70 bound to purified MTs with a stoichiometry of 0.40 +/- 0.04 mol of ELP70/mol of tubulin dimer and with an intrinsic dissociation constant of 0.44 +/- 0.13 microm. Using a nucleated assembly assay and video-enhanced differential interference contrast microscopy, we demonstrated that ELP70 reduced seeded nucleation, reduced the growth rate, and promoted MT catastrophes in a concentration-dependent manner. As a result, ELP70-containing MTs were significantly shorter than MTs assembled from tubulin alone. These data indicate that ELP70 is a novel MT destabilizer. A lateral destabilization model is presented to describe ELP70's effects on microtubules.