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ONO-4685-04:ONO-4685 Phase 1 study Single intravenous continuous infusion and subcutaneous administration study in Japanese healthy adult male subjects

ONO-4685-04: ONO-4685 Phase 1 study

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This study was conducted on healthy Japanese men between the age of 18 and 45.

This study is a single-center, placebo-controlled, randomized, single-blind, parallel-group comparative study to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of ONO-4685 when administered by single-dose continuous intravenous infusion and single-dose subcutaneous injection in Japanese healthy adult males. This study was conducted in a study design to escalate the ONO-4685 dose in each Part (Part A [continuous intravenous administration part], Part B [subcutaneous administration part]). In the Part A, 24 subjects were participated as total: six active and 2 placebo in each cohort (the Cohort A1, A2 and A3). In the Part B, 8 subjects were participated as total: six active and 2 placebo in cohort B1. There were no subjects who discontinued/dropped out in any Part.

In the Part A, adverse events were not observed in the placebo treatment group and the Cohort A1, catheter site vasculitis was observed in 1/6 subjects (16.7%) in the Cohort A2, and cytokine release syndrome and lymphocyte count decreased were observed in 6/6 subjects (100.0%) each in the Cohort A3. In terms of severity of adverse events, lymphocyte count decreased observed in 6 subjects in the Cohort A3 was Grade 4 in 1 subject and Grade 3 in 5 subjects, but the other events were Grade 1. Cytokine release syndrome observed in 5 subjects in the Cohort A3 resolved after prescription of acetaminophen, and the other events resolved without treatment. Grade 4 and Grade 3 lymphocyte count decreased observed in 6 subjects in the Cohort A3 all occurred on Day 1 of treatment with ONO-4685 but resolved without treatment on Day 3 or Day 4 after occurrence. Cytokine release syndrome and lymphocyte count decreased observed in 6/6 subjects (100.0%) each in the Cohort A3 were all judged to be adverse reactions. In the Part B, No adverse events were observed in the placebo treatment group, whereas injection site erythema was observed in 6/6 subjects (100.0%), injection site pruritus in 4/6 subjects (66.7%), and injection site pain, lymphadenopathy, cytokine release syndrome, lymphangitis, and C-reactive protein increased in 1/6 subjects (16.7%) each in the Cohort B1. In terms of severity of adverse events, injection site erythema and injection site pain observed in 1 subject in the Cohort B1 were Grade 2, but the other events were Grade 1. Injection site pain and cytokine release syndrome observed in 1 subject each in the Cohort B1 resolved after the prescription of acetaminophen, and the other events resolved without treatment. The adverse events observed in the Cohort B1 were all judged to be adverse reactions.

In the Part A, the safety, pharmacokinetics, pharmacodynamics, and immunogenicity were evaluated in Japanese healthy adult males to whom ONO-4685 was administered by single-dose continuous intravenous infusion over 1 hour, with placebo as a control. The results showed that no adverse events were observed in the placebo treatment group and the Cohort A1, whereas catheter site vasculitis was observed in 1/6 subjects (16.7%) in the Cohort A2, and cytokine release syndrome and lymphocyte count decreased were observed in 6/6 subjects (100.0%) each in the Cohort A3. In terms of the severity of adverse events, lymphocyte count decreased observed in 6 subjects in the Cohort A3 was Grade 4 in 1 subject and Grade 3 in 5 subjects, but other events were Grade 1. Cytokine release syndrome observed in 5 subjects in the Cohort A3 resolved after prescription of acetaminophen, and the other events resolved without treatment. Grade 4 and Grade 3 lymphocyte count decreased observed in 6 subjects in the Cohort A3 all occurred on Day 1 of treatment with ONO-4685 but resolved without treatment on Day 3 or Day 4 after occurrence. Cytokine release syndrome and lymphocyte count decreased observed in 6/6 subjects (100.0%) each in the Cohort A3 were all judged to be adverse reactions. The plasma ONO-4685 concentration reached a peak at the end of infusion and decreased rapidly after the end of administration at all doses. Although the dose per kg body weight and the total dose were dose proportional to the Cmax, the confidence interval of the slope of the regression equation did not include 1 with AUClast, showing positive nonlinearity. In the Cohort A1 and A2, no significant increase after the study drug treatment was observed for each evaluated cytokine (IL-2, IL-6, IL-10, IFN-gamma, and TNF-alpha), and cytokine release syndrome was not observed. In addition, for each lymphocyte subset (CD4-positive lymphocyte, CD8-positive lymphocyte, B cell, and NK cell) that was evaluated, no significant fluctuation was observed after study drug treatment. On the other hand, in the Cohort A3, significant increases were observed in all cytokines evaluated on Day 1 of treatment, and cytokine release syndrome was observed in 6/6 subjects (100.0%). Significant decreases in all evaluated lymphocyte subsets were also observed on Day 1 of treatment, and lymphocyte count decreased was observed as an adverse event in 6/6 subjects (100.0%). In the Cohort A1 and A2, no antibodies against ONO-4685 were detected, whereas in the Cohort A3, 2/6 subjects (33.3%) were positive for anti-ONO-4685 antibodies on Day 28 of treatment, and these results were observed until Day 84 of treatment. In the Part B, the safety, pharmacokinetics, pharmacodynamics, and immunogenicity were evaluated in Japanese healthy adult males to whom ONO-4685 was administered by single-dose subcutaneous injection, with placebo as a control. The results showed that no adverse events were observed in the placebo treatment group, whereas injection site erythema was observed in 6/6 subjects (100.0%), injection site pruritus in 4/6 subjects (66.7%), and injection site pain, lymphadenopathy, cytokine release syndrome, lymphangitis, and C-reactive protein increased in 1/6 subjects (16.7%) each in the Cohort B1. In terms of severity of adverse events, injection site erythema and injection site pain observed in 1 subject in the Cohort B1 were Grade 2, but the other events were Grade 1. Injection site pain and cytokine release syndrome observed in 1 subject each in the Cohort B1 resolved after the prescription of acetaminophen, and the other events resolved without treatment. The adverse events observed in the Cohort B1 were all judged to be adverse reactions. Plasma ONO-4685 concentrations reached a peak after single-dose subcutaneous injection on Days 1 to 2 of treatment and then decreased slowly. In the Cohort B1, significant increases were observed in each cytokine (IL-6, IL-10, IFN-gamma, and TNF-alpha) except IL-2 on Day 1 of treatment, and cytokine release syndrome was observed in 1/6 subjects (16.7%). For each lymphocyte subset (CD4-positive lymphocyte, CD8-positive lymphocyte, B cell, and NK cell) evaluated, no significant fluctuation was observed after study drug treatment. In the Cohort B1, all subjects (6/6 subjects [100.0%]) were positive for anti-ONO-4685 antibodies on Day 28 of treatment, and antibodies were continuously observed until Day 84 of treatment in 5 subjects.

When ONO-4685 was administered by single-dose continuous intravenous infusion within 3 doses, the pharmacokinetics showed dose proportionality. Moreover, in low dose and middle dose, no significant changes were observed in cytokines or lymphocyte counts, and tolerability was shown. On the other hand, when ONO-4685 was administered by single-dose continuous intravenous infusion at high dose, cytokine release syndrome and lymphocyte count decreased were observed as adverse reactions, but tolerability was show

July. 25, 2025

No

https://jrct.mhlw.go.jp/latest-detail/jRCT2071220081

Namba Yoshinobu

Ono Pharmaceutical Co.,LTD

3 -1 -1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka

clinical_trial@ono-pharma.com

Medical Information Center

Ono Pharmaceutical Co.,LTD

3 -1 -1 Sakurai, Shimamoto-cho, Mishima-gun, Osaka

+81-120-626-190

clinical_trial@ono-pharma.com

Complete

Dec. 23, 2022

Interventional

non-randomized controlled trial

single blind

placebo control

parallel assignment

treatment purpose

1) Japanese healthy adult male subjects
2) Age at the time of informed consent: 18 to 45
3) BMI (at screening): 18.5 kg/m2 to less than 25.0 kg/m2

1) Subjects who are on a treatment for or with a history of respiratory, cardiovascular, psychiatric, neurologic, gastrointestinal, immunologic, hepatic, renal, hematopoietic or endocrine and/or other disease.
2) Subjects with current or with a history of severe allergy to drugs or foods
3) Subjects with current or with a history of drug or alcohol abuse

Male

Auto immune disease

ONO-4685:Single-dose intravenous continuous infusion and subcutaneous administration

Safety, Pharmacokinetics

Pharmacodynamics,Immunogenicity

+81-92-283-7701

Dec. 15, 2022

none