Phase I and scintigraphy studies to evaluate safety, tolerability, pharmacokinetics, and lung deposition of inhaled GDC-0214 in healthy volunteers.

Several inflammatory cytokines that promote inflammation and pathogenesis in asthma signal through the Janus kinase 1 (JAK1) pathway. This phase I, randomized, placebo-controlled trial assessed the pharmacokinetics and safety of single and multiple ascending doses up to 15 mg twice daily for 14 days of a JAK1 inhibitor, GDC-0214, in healthy volunteers (HVs; n = 66). Doses were administered with a dry powder, capsule-based inhaler. An accompanying open-label gamma scintigraphy study in HVs examined the lung deposition of a single dose of inhaled Technetium-99m (99m Tc)-radiolabeled GDC-0214. GDC-0214 plasma concentrations were linear and approximately dose-proportional after both single and multiple doses. Peak plasma concentrations occurred at 15-30 min after dosing. The mean apparent elimination half-life ranged from 32 to 56 h across all single and multiple dose cohorts. After single and multiple doses, all adverse events were mild or moderate, and none led to treatment withdrawal. There was no clear evidence of systemic toxicity due to JAK1 inhibition, and systemic exposure was low, with plasma concentrations at least 15-fold less than the plasma protein binding-corrected IC50 of JAK1 at the highest dose. Scintigraphy showed that approximately 50% of the emitted dose of radiolabeled GDC-0214 was deposited in the lungs and was distributed well to the peripheral airways. 99m Tc-radiolabeled GDC-0214 (1 mg) exhibited a mean plasma Cmax similar to that observed in phase I at the same dose level. Overall, inhaled GDC-0214 exhibited pharmacokinetic properties favorable for inhaled administration.

Efficacy, Safety, and Pharmacodynamic Effects of the Bruton's Tyrosine Kinase Inhibitor Fenebrutinib (GDC-0853) in Systemic Lupus Erythematosus: Results of a Phase II, Randomized, Double-Blind, Placebo-Controlled Trial.

OBJECTIVE: Fenebrutinib (GDC-0853) is a noncovalent, oral, and highly selective inhibitor of Bruton's tyrosine kinase (BTK). The efficacy, safety, and pharmacodynamics of fenebrutinib in systemic lupus erythematosus (SLE) were assessed in this phase II, multicenter, randomized, placebo-controlled study. METHODS: Patients who had moderately to severely active SLE while receiving background standard therapy were randomized to receive placebo, fenebrutinib 150 mg once daily, or fenebrutinib 200 mg twice daily. Glucocorticoid taper was recommended from weeks 0 to 12 and from weeks 24 to 36. The primary end point was the SLE Responder Index 4 (SRI-4) response at week 48. RESULTS: Patients (n = 260) were enrolled from 44 sites in 12 countries, with the majority from Latin America, the US, and Western Europe. The SRI-4 response rates at week 48 were 51% for fenebrutinib 150 mg once daily (P = 0.37 versus placebo), 52% for fenebrutinib 200 mg twice daily (P = 0.34 versus placebo), and 44% for placebo. British Isles Lupus Assessment Group-based Combined Lupus Assessment response rates at week 48 were 53% for fenebrutinib 150 mg once daily (P = 0.086 versus placebo), 42% for fenebrutinib 200 mg twice daily (P = 0.879 versus placebo), and 41% for placebo. Safety results were similar across all arms, although serious adverse events were more frequent with fenebrutinib 200 mg twice daily. By week 48, patients treated with fenebrutinib had reduced levels of a BTK-dependent plasmablast RNA signature, anti-double-stranded DNA autoantibodies, total IgG, and IgM, as well as increased complement C4 levels, all relative to placebo. CONCLUSION: While fenebrutinib had an acceptable safety profile, the primary end point, SRI-4 response, was not met despite evidence of strong pathway inhibition.

Influence of Baseline Cardiovascular Comorbidities on Mortality after Androgen Deprivation Therapy for Metastatic Prostate Cancer.

Few studies have assessed the benefits of androgen deprivation therapy (ADT) in men with metastatic prostate cancer (PC; mPC) at an old age or with major cardiovascular conditions. A retrospective cohort consisted of 3835 men with newly diagnosed mPC from the Taiwan Cancer Registry of 2008-2014. Among them, 2692 patients received only ADT in the first year after the cancer diagnosis, and 1143 patients were on watchful waiting. The inverse probability of treatment-weighted Cox model was used to estimate the effects of ADT on all-cause mortality and PC-specific mortality according to age, and the status of congestive heart failure (CHF), coronary arterial diseases (CADs), and stroke at the baseline. After a median follow-up of 2.65 years, 1650 men had died. ADT was associated with a 17-22% risk reduction in all-cause and PC-specific mortality in men without stroke, CAD, or CHF in the 65-79-year group. The survival benefit diminished in men with any of these preexisting conditions. In contrast, ADT was not found to be associated with any survival benefit in the ≥80-year group, even though they did not present with any major cardiovascular disease at the baseline. Patients who had CHF, CAD, or stroke at the baseline did not show a survival benefit following ADT in any of the age groups. Men who have preexisting major cardiovascular diseases or are ≥80 years do not demonstrate a survival benefit from ADT for mPC. The risk-benefit ratio should be considered when using ADT for mPC in older men especially those with major cardiovascular comorbidities.

Role of NADPH oxidase in radiation-induced pro-oxidative and pro-inflammatory pathways in mouse brain.

PURPOSE: The present study was designed to investigate our hypothesis that NADPH oxidase plays a role in radiation-induced pro-oxidative and pro-inflammatory environments in the brain. MATERIALS AND METHODS: C57BL/6 mice received either fractionated whole brain irradiation or sham-irradiation. The mRNA expression levels of pro-inflammatory mediators, such as TNF-α and MCP-1, were determined by quantitative real-time RT-PCR. The protein expression levels of TNF-α, MCP-1, NOX-2 and Iba1 were detected by immunofluorescence staining. The levels of ROS were visualized by in situ DHE fluorescence staining. RESULTS: A significant up-regulation of mRNA and protein expression levels of TNF-α and MCP-1 was observed in irradiated mouse brains. Additionally, immunofluorescence staining of Iba1 showed a marked increase of microglial activation in mouse brain after irradiation. Moreover, in situ DHE fluorescence staining revealed that fractionated whole brain irradiation significantly increased production of ROS. Furthermore, a significant increase in immunoreactivity of NOX-2 was detected in mouse brain after irradiation. On the contrary, an enhanced ROS generation in mouse brain after irradiation was markedly attenuated in the presence of NOX inhibitors or NOX-2 neutralizing antibody. CONCLUSIONS: These results suggest that NOX-2 may play a role in fractionated whole brain irradiation-induced pro-oxidative and pro-inflammatory pathways in mouse brain.

Anti-EGFL7 antibodies enhance stress-induced endothelial cell death and anti-VEGF efficacy.

Many oncology drugs are administered at their maximally tolerated dose without the knowledge of their optimal efficacious dose range. In this study, we describe a multifaceted approach that integrated preclinical and clinical data to identify the optimal dose for an antiangiogenesis agent, anti-EGFL7. EGFL7 is an extracellular matrix-associated protein expressed in activated endothelium. Recombinant EGFL7 protein supported EC adhesion and protected ECs from stress-induced apoptosis. Anti-EGFL7 antibodies inhibited both of these key processes and augmented anti-VEGF-mediated vascular damage in various murine tumor models. In a genetically engineered mouse model of advanced non-small cell lung cancer, we found that anti-EGFL7 enhanced both the progression-free and overall survival benefits derived from anti-VEGF therapy in a dose-dependent manner. In addition, we identified a circulating progenitor cell type that was regulated by EGFL7 and evaluated the response of these cells to anti-EGFL7 treatment in both tumor-bearing mice and cancer patients from a phase I clinical trial. Importantly, these preclinical efficacy and clinical biomarker results enabled rational selection of the anti-EGFL7 dose currently being tested in phase II clinical trials.

Impaired T cell function in RANTES-deficient mice.

The chemokine RANTES is a chemoattractant for monocytes and T cells and is postulated to participate in many aspects of the immune response. To evaluate the biological roles of RANTES in vivo, we generated RANTES-deficient (-/-) mice and characterized their T cell function. In cutaneous delayed-type hypersensitivity assays, a 50% reduction in ear and footpad swelling was seen in -/- mice compared to +/+ mice. In vitro, polyclonal and antigen-specific T cell proliferation was decreased. Quantitative analysis using the fluorescent dye carboxy-fluorescein succinimidyl ester revealed that this proliferative defect was due both to fewer antigen-reactive T cells and to a reduction in the capacity of these cells to proliferate. In addition, IFN-gamma and IL-2 production by the -/- T cells was dramatically decreased. Together, these data suggest that RANTES is required for normal T cell functions as well as for recruiting monocytes and T cells to sites of inflammation.