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. Subjects who completed the evaluation at Week 24 of the treatment phase were rolled over into the extension phase. The extension phase lasted until Week 104, and all subjects received E6011 400 mg or 200 mg every 2 weeks in an open-label manner until Week 102. RESULTS: A total of 47 subjects completed the double-blind treatment phase and were rolled over into the extension phase. In total, 46 (97.9%) subjects experienced any adverse events, and the incidence of treatment-related adverse events was 57.4%. No clear efficacy trend in the American College of Rheumatology 20% response rates was observed. CONCLUSIONS: E6011 was well tolerated in active rheumatoid arthritis patients who had shown an inadequate response to biologic disease-modifying antirheumatic drugs, but no clear benefit in the American College of Rheumatology 20% response rates was observed. Further studies are needed to clarify the clinical benefit of E6011.

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. The safety analysis was conducted up to Week 104, and the efficacy analysis was conducted up to Week 84. RESULTS: A total of 169 subjects completed the double-blind treatment phase and were rolled over into the extension phase. In total, 167 (98.8%) subjects experienced any adverse events, and the incidence of treatment-related adverse events was 56.2%. The American College of Rheumatology 20 response rates were observed between 40 and 70% during the extension phase. CONCLUSIONS: E6011 was safe and well tolerated with no notable safety concerns up to 102 weeks in RA patients with an inadequate response to MTX.

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. RESULTS: Of 64, 33 received placebo, 31 received E6011 400-mg. The ACR20 response rate at week 12 (non-responder imputation) was 27.3% and 22.6% in the placebo and E6011 groups, respectively. ACR50, ACR70 response rates at week 12 were 3.0%, 0% in the placebo and 9.7%, 3.2% in the E6011 group. Exploratory PK exposure analysis revealed that the effect of E6011 tended to be clearer in patients with higher serum trough E6011 concentration. E6011 was well tolerated with no notable safety concerns. CONCLUSIONS: E6011 400-mg was well tolerated but had no clear efficacy at week 12 in RA patients with inadequate response to biologics. Further investigations are warranted to determine the optimal clinical dose and evaluation period for E6011.

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). METHODS: Active RA patients with an inadequate response or intolerance to methotrexate or tumor necrosis factor (TNF) inhibitor received E6011 at week 0, 1, 2, and thereafter every 2 weeks for 12 weeks. RESULTS: Twelve, 15, and 10 subjects were enrolled in the 100, 200, and 400 mg cohorts, respectively. No severe adverse events (AEs) or deaths occurred, and no major differences were observed in the incidence or severity of AEs across the cohorts. Serum E6011 concentrations increased dose dependently. American College of Rheumatology (ACR) 20, 50, and 70 responses at week 12 were 75.0%, 33.3%, and 8.3% in the 100 mg cohort; 66.7%, 20.0%, and 13.3% in the 200 mg cohort; and 60.0%, 30.0%, and 20.0% in the 400 mg cohort, respectively. CONCLUSIONS: E6011 appeared to be safe and well tolerated in RA patients during this 12-week treatment period, suggesting that E6011 has an effective clinical response in active RA patients.

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. E6742 was rapidly absorbed with a median tmax ranging from 1.50 to 2.50 hours across dose groups under the fasted condition, and eliminated with a median t½ ranging from 2.37 to 14.4 hours. After multiple oral doses, a steady state was reached by day 7. In the SAD study, dose proportionality was observed for Cmax , AUC(0-t) , and AUC(0-inf) values of E6742 up to 800 mg, but these values were slightly less than dose proportional at 10 mg. In the MAD study, the Cmax and AUC(0-12h)ss of E6742 appeared to be almost dose proportionally increased between 100 and 200 mg, while these parameters showed more than a dose proportional increase at 400 mg. In addition to safety and good tolerability, this study demonstrated cytokine concentrations in cultured peripheral blood in response to E6742 were suppressed in a dose-dependent manner. Further clinical studies targeting systemic lupus erythematosus patients are currently underway.

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. The primary end point was the American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 12. RESULTS: Study drugs were administered to 190 patients (placebo, n = 54; E6011 100 mg, n = 28; E6011 200 mg, n = 54; E6011 400/200 mg, n = 54), and 169 patients completed treatment. A significant difference from placebo was not found in ACR20 response rates at week 12 (37.0% [placebo], 39.3% [100 mg], 48.1% [200 mg], and 46.3% [400/200 mg], using nonresponder imputation). As a secondary end point, ACR20 response rate in the 200-mg and 400/200-mg groups attained statistical significance at week 24 (35.2% [placebo], 39.3% [100 mg], 53.7% [200 mg], and 57.4% [400/200 mg]). Subsequent exploratory subgroup analysis revealed greater efficacy of E6011, particularly in patients with a higher baseline proportion of CD16+ monocytes; ACR20 response rates in this patient subgroup at week 24 were 30.0% (placebo), 46.7% (100 mg), 57.7% (200 mg), and 69.6% (400/200 mg). E6011 administered for 24 weeks was well tolerated. CONCLUSION: This is the first evidence that E6011, a novel cell trafficking inhibitor targeting the FKN-CX3 CR1 interaction, is modestly effective with 24 weeks of treatment in RA patients, although the primary end point was not met.

Pharmacokinetic disposition of topical phosphodiesterase-4 inhibitor E6005 in patients with atopic dermatitis.

Background: A novel topical phosphodiesterase-4 inhibitor E6005 shows potential as effective treatment option for atopic dermatitis (AD); however, systemic exposure may cause potentially undesirable adverse reactions. In this study, we evaluated the relationship between the systemic exposure of E6005 and clinical parameters including skin condition and the incidence of AEs in patients with AD. Methods: The association analysis used the clinical data obtained in a previously conducted clinical study with topical E6005 in adult patients with AD. To estimate associations with drug exposure, generalized estimating equation logistic regression models were used, along with clinical data and plasma concentrations of M11, the major metabolite of E6005 (as an indicator for E6005 exposure). Results: The metabolite M11 was detected in 62 of 221 plasma samples from 72 subjects. From association analysis, SCORAD-A obtained prior to E6005 treatment was identified as the clinical parameter influenced to M11 detection with statistical significance (p = .003). M11 detection was not clearly associated with the incidence of adverse events occurred. Conclusion: Exposure to topical E6005 is associated with the eczema-associated area, however, that is not distinctly associated with its adverse drug reactions occurred after drug applications possibly due to E6005's characteristics of tissue distribution.

Effect of topical phosphodiesterase 4 inhibitor E6005 on Japanese children with atopic dermatitis: Results from a randomized, vehicle-controlled exploratory trial.

This exploratory study was designed to evaluate the safety and efficacy profile of the topical phosphodiesterase 4 inhibitor E6005 in Japanese children with mild-to-moderate atopic dermatitis. The present randomized, multicenter study included 62 patients who were treated with 0.05% E6005, 0.2% E6005 or vehicle ointment twice daily for 2 weeks. Safety and pharmacokinetics were assessed with a focus on the occurrence of adverse events and the whole blood concentrations of E6005 and its metabolite. Exploratory efficacy evaluations included assessments of lesion severity and pruritus score. The 2-week application of topical E6005 was safe and well tolerated with no cutaneous adverse events. The whole blood concentration of E6005 was quantified in only one subject receiving 0.2% E6005 treatment, while its major metabolite was undetectable. The 0.2% E6005 group showed a greater decrease in the severity score than the vehicle group (-45.94% vs -32.26%), although this difference was not statistically significant. Similarly, the treatment success rate according to the investigator's global assessment of the total application sites was higher in the 0.2% E6005 group than in the vehicle group (34.4% vs 20.0%). Moreover, the 0.2% E6005 group showed a greater decrease in the pruritus score than the vehicle group (-37.5% vs -6.7%) in a predefined subpopulation. The efficacy of 0.05% E6005 treatment was comparable to that of vehicle treatment. These results suggest that topical 0.2% E6005 treatment is safe and effective in children with atopic dermatitis, although further large confirmatory clinical trials are warranted.

Targeted prevention of renal accumulation and toxicity of gentamicin by aminoglycoside binding receptor antagonists.

Receptor-mediated endocytosis plays an important role in accumulation of aminoglycosides in renal proximal tubule. To prevent aminoglycoside-induced nephrotoxicity following concentrated accumulation of gentamicin in the kidney, effect of cationic proteins and their peptide fragments, which could inhibit gentamicin binding to its binding receptor(s), was investigated. Among several substrates for megalin, an endocytic receptor responsible for renal accumulation of aminoglycosides, cytochrome c potently inhibited gentamicin accumulation in renal cortex. Concentration-dependent inhibition by cytochrome c on gentamicin uptake was also observed in OK kidney epithelial cells expressing megalin. In addition, gentamicin-induced increase in urinary excretion of N-acetyl-beta-d-glucosaminidase (NAG), a marker of renal tubular damage, was significantly reduced by cytochrome c. We next attempted to find a peptide fragment with lower molecular size showing inhibitory effect on gentamicin uptake. Cyto79-88 inhibited gentamicin uptake in OK cells, but had little effect on renal accumulation of gentamicin in mice in vivo. On one hand, a peptide fragment of neural Wiskott-Aldrich syndrome protein (N-WASP), which interacts with acidic phospholipids like aminoglycosides, inhibited gentamicin accumulation not only in OK cells but also in mouse kidney. These results show that substrates and/or their peptide fragments for aminoglycoside binding receptor such as megalin might be useful for preventing aminoglycoside-induced nephrotoxicity.

Safety and efficacy of topical E6005, a phosphodiesterase 4 inhibitor, in Japanese adult patients with atopic dermatitis: results of a randomized, vehicle-controlled, multicenter clinical trial.

The safety and efficacy of topical E6005, a novel phosphodiesterase 4 inhibitor, in Japanese adults with atopic dermatitis were evaluated. A total of 78 patients were randomized to receive either the 0.2% E6005 ointment or vehicle control (without E6005) at an allocation ratio of 2:1. The randomization phase of 4 weeks was followed by an extension phase of 8 weeks. In the extension phase, all 67 subjects who completed the randomization phase were treated with 0.2% E6005 ointment. The 4-week application of topical E6005 twice daily was safe and well tolerated. The safety profile for up to 12 weeks was similar to that for the first 4 weeks. No deaths or other serious adverse effects were observed during the entire study period of 12 weeks. Plasma E6005 was undetectable in all subjects at all sampling points while very low plasma concentrations of an E6005 metabolite were detected in 47% of subjects receiving E6005 treatment. At the end of week 4, Eczema Area and Severity Index (EASI), Severity Scoring Atopic Dermatitis (SCORAD)-objective, SCORAD-C (visual analog scales for pruritus and sleep loss), itch Behavioral Rating Scale, and the severity of the targeted eczematous lesions in the topical E6005 group showed trends toward improvement compared with those in the vehicle group (not statistically significant). However, the group receiving topical E6005 for 12 weeks showed significant score reductions from baselines for EASI (P = 0.030), SCORAD-objective (P < 0.001) and SCORAD-C (P = 0.038). These results further support the development of topical E6005 for the treatment of atopic dermatitis.

Safety, pharmacokinetics and pharmacodynamics of four-hour intravenous infusions of eritoran in healthy Japanese and Caucasian men.

Eritoran, a synthetic analogue of lipid A, has been shown to bind to TLR4/MD-2 complex and thereby block the interaction of endotoxins with TLR4. We report here the results of a study conducted to assess the single-dose safety and tolerability, as well as the pharmacokinetics and pharmacodynamics, of eritoran infusion in Japanese and Caucasian healthy adult men. Sixty-four men (aged 20-45 years; body mass index 18-30 kg/m(2)) were randomized into four groups: 4-mg total dose (six Japanese and six Caucasian men); 12-mg total dose (12 Japanese and 12 Caucasian men); 28-mg total dose (six Japanese and six Caucasian men); and placebo (eight Japanese and eight Caucasian men). Eritoran in single doses up to 28 mg over 4 h was well tolerated, with no apparent ethnic differences noted. Plasma concentrations were slightly higher in Japanese versus Caucasian men; these differences were not significant after adjustment for differences in body mass (clearance: approximately 1.2 ml/h/kg; volume of distribution at steady state: approximately 0.07 l/kg). The ex vivo endotoxin inhibitory activity of eritoran was similar in Japanese and Caucasian men. The data do not indicate any need for clinical dose adjustment for possible ethnic-based differences in drug distribution or metabolism.

Cisplatin-induced inhibition of receptor-mediated endocytosis of protein in the kidney.

BACKGROUND: Administration of cisplatin, cis-diamminedichloroplatinum (II) (CDDP), causes a severe impairment of renal function, including increases in urinary excretion of proteins. We recently found that CDDP inhibits vacuolar H+-ATPase, which plays an important role in receptor-mediated endocytosis in the renal proximal tubules. Therefore, CDDP-induced proteinuria may be due to an inhibition of the receptor-mediated endocytosis in the renal proximal tubules following a decrease in vacuolar H+-ATPase activity by the drug. METHODS: Effects of CDDP on receptor-mediated endocytosis of albumin in opossum kidney (OK) epithelial cells, and on urinary excretion of albumin and vitamin D binding protein, which are reabsorbed in the renal proximal tubules by endocytosis, in rats were examined. RESULTS: CDDP inhibited uptake of fluorescein-isothiocyanate (FITC)-albumin, a receptor-mediated endocytosis marker, by OK cells in a time- and concentration-dependent fashion. In contrast, CDDP treatment did not affect the uptake of FITC-inulin, a fluid-phase endocytosis marker. CDDP caused a decrease in the affinity and in the maximal velocity of FITC-albumin uptake. The adenosine 5'-triphosphate (ATP) content in OK cells was not changed by CDDP at concentrations that inhibited FITC-albumin uptake. The endosomal pH in OK cells was increased by CDDP treatment. Administration of CDDP to rats increased the urinary excretion of albumin and vitamin D binding protein. CONCLUSIONS: These results suggest that CDDP decreases the receptor-mediated endocytosis of protein following the inhibition of vacuolar H+-ATPase in the renal proximal tubules, and the inhibition of receptor-mediated endocytosis would be the mechanisms underlying the proteinuria induced by CDDP.