Safety, pharmacokinetics, biomarker response and efficacy of E6742: a dual antagonist of Toll-like receptors 7 and 8, in a first in patient, randomised, double-blind, phase I/II study in systemic lupus erythematosus.

Objectives: To evaluate the safety, tolerability, pharmacokinetics (PK), biomarker response and efficacy of E6742 in a phase I/II study in patients with systemic lupus erythematosus (SLE).

Methods: Two sequential cohorts of patients with SLE were enrolled and randomised to 12 weeks of two times per day treatment with E6742 (100 or 200 mg; n=8 or 9) or placebo (n=9). The primary endpoint was safety, the secondary endpoints were PK and interferon gene signature (IGS), and the exploratory endpoints were efficacy and biomarker.

A new therapeutic target for systemic lupus erythematosus: the current landscape for drug development of a toll-like receptor 7/8 antagonist through academia-industry-government collaboration.

Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by inflammation in multiple organs. A few treatments for SLE currently exist, including antimalarials, glucocorticoids, immunosuppressants, and two recently approved antibody agents; however, an unmet medical need remains for SLE. In addition, developing new drugs targeting SLE is a challenge since no specific biomarkers exist for the prediction of disease progression or drug response.

A novel Toll-like receptor 7/8-specific antagonist E6742 ameliorates clinically relevant disease parameters in murine models of lupus.

The sensing of self RNA by the endosomal Toll-like receptors (TLRs) 7 and 8 initiates pathogenic mechanisms underlying the autoimmune disease lupus. A blockade of the TLR7/8 signals may, therefore, be a novel therapeutic intervention for lupus. To test the hypothesis, a novel compound E6742 that blocks TLR7/8 activation was identified.

Long-term safety and efficacy of E6011, an anti-fractalkine monoclonal antibody, in patients with rheumatoid arthritis inadequately responding to methotrexate.

Objectives: To evaluate the long-term safety and efficacy of E6011, a humanized anti-fractalkine monoclonal antibody, in patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX).

Methods: Active RA patients with an inadequate response to MTX were randomly assigned to the E6011 or placebo group and received the study drug subcutaneously every 2 weeks during a 24-week double-blind study period. Subjects who completed evaluations at Week 24 were rolled over into the extension phase and received open-label E6011 (200 or 400 mg) every 2 weeks until Week 102.

Long-term evaluation of E6011, an anti-fractalkine monoclonal antibody, in patients with rheumatoid arthritis inadequately responding to biological disease-modifying antirheumatic drugs.

Objectives: The objective of the study is to evaluate the long-term safety and efficacy of E6011, a humanized anti-fractalkine monoclonal antibody, in patients with rheumatoid arthritis with an inadequate response to biological disease-modifying antirheumatic drugs.

Methods: In the double-blind treatment phase (24 weeks), placebo or E6011 400 mg was administered until Week 10. Thereafter, E6011 200 mg or 400 mg was administered to Week 22.

First-in-Human Study of the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of E6742, a Dual Antagonist of Toll-like Receptors 7 and 8, in Healthy Volunteers.

The first-in-human phase I study for E6742, a dual toll-like receptor (TLR) 7 and TLR8 antagonist, has been conducted to assess the safety, tolerability, and pharmacokinetics of E6742 in healthy volunteers. In a single ascending dose (SAD) study, 42 subjects received 10-800 mg of E6742 in the fasted state, as well as a 100-mg cohort in the fed state for evaluating the effect of food. In a multiple ascending dose (MAD) study, 18 subjects received 100-400 mg of E6742 twice daily for 7 days.

A phase 2 study of E6011, an anti-Fractalkine monoclonal antibody, in patients with rheumatoid arthritis inadequately responding to biological disease-modifying antirheumatic drugs.

Objectives: To evaluate the safety and efficacy of E6011, a novel humanized anti-fractalkine monoclonal antibody, in patients with active rheumatoid arthritis (RA) with an inadequate response to biological disease-modifying antirheumatic drugs (DMARDs).

Methods: Active RA patients inadequately responding to biological DMARDs were randomly assigned to placebo or E6011 400-mg group at a 1:1 ratio, and administered E6011 at weeks 0, 1, 2, and subsequently every 2 weeks. Primary endpoint was American College of Rheumatology (ACR)20 response at week 12.

Efficacy and Safety of E6011, an Anti-Fractalkine Monoclonal Antibody, in Patients With Active Rheumatoid Arthritis With Inadequate Response to Methotrexate: Results of a Randomized, Double-Blind, Placebo-Controlled Phase II Study.

Objective: To evaluate the efficacy and safety of E6011, a humanized IgG2 monoclonal antibody against human fractalkine (FKN), in a phase II, double-blind, placebo-controlled study in rheumatoid arthritis (RA) patients.

Methods: Patients with moderate-to-severe RA who had an inadequate response to methotrexate were randomly assigned to a placebo group or to E6011 100-mg, 200-mg, or 400/200-mg groups at a 2:1:2:2 ratio. During the 24-week period, patients received the study drug subcutaneously at weeks 0, 1, and 2 and then once every 2 weeks.

Safety, pharmacokinetics, and efficacy of E6011, an antifractalkine monoclonal antibody, in a first-in-patient phase 1/2 study on rheumatoid arthritis.

Objective: Fractalkine (CX3CL1/FKN) is a chemokine that regulates chemotaxis and adhesion of CX3C chemokine receptor 1 (CX3CR1)-expressing inflammatory cells. We conducted the first phase 1/2, open-label, multiple ascending dose study of E6011, a humanized anti-FKN monoclonal antibody, in Japanese rheumatoid arthritis (RA) patients (clinicaltrial.gov identifier: NCT02196558).

Suppressing effect of low-dose gamma-ray irradiation on collagen-induced arthritis.

We previously reported attenuation of autoimmune disease by low-dose gamma-ray irradiation in MRL-lpr/lpr mice. Here, we studied the effect of low-dose gamma-ray irradiation on collagen-induced arthritis (CIA) in DBA/1J mice. Mice were immunized with type II collagen, and exposed to low-dose gamma-rays (0.

Repeated 0.5-Gy gamma irradiation attenuates autoimmune disease in MRL-lpr/lpr mice with suppression of CD3+CD4-CD8-B220+ T-cell proliferation and with up-regulation of CD4+CD25+Foxp3+ regulatory T cells.

Tago, F., Tsukimoto, M., Nakatsukasa, H.

Repeated 0.5-Gy gamma-ray irradiation attenuates autoimmune manifestations in MRL-lpr/lpr mice.

Purpose: MRL-lpr/lpr mice, a model for various autoimmune diseases, were repeatedly irradiated with 0.5 Gy of gamma-rays, and changes in their autoimmune manifestations were investigated.

Materials And Methods: MRL-lpr/lpr mice at 13 weeks of age were maintained in plastic cages and exposed whole-body to 0.

Repeated irradiations with gamma-rays at a Dose of 0.5 Gy may exacerbate asthma.

We previously showed that 0.5 Gy whole-body gamma-ray irradiation with a single or small number of repeated exposures inhibits tumor growth in mice, via elevation of the IFN-gamma/IL-4 ratio concomitantly with a decrease in the percentage of B cells. Here we examined whether repeated 0.