Juan Zhang, Yu-Xin Fan, Yu Huang, Runfang Guan, Ruixia Li, Shuxian Long, Mei Yang, Binge Yu, Guo Qin Wang, Peng Chen, Xia Gong, Baiyong Li, Michelle Xia, Jianchang He
{"title":"健康受试者单次皮下注射抗ngf单克隆抗体（AK115）的安全性、耐受性、药代动力学和药效学：一项随机、双盲、安慰剂对照、剂量递增的I期临床试验","authors":"Juan Zhang, Yu-Xin Fan, Yu Huang, Runfang Guan, Ruixia Li, Shuxian Long, Mei Yang, Binge Yu, Guo Qin Wang, Peng Chen, Xia Gong, Baiyong Li, Michelle Xia, Jianchang He","doi":"10.2147/DDDT.S500902","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to investigate the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of a novel anti-nerve growth factor (NGF) monoclonal antibody (mAb) (AK115) in healthy Chinese participants.</p><p><strong>Methods: </strong>A randomized, double-blind, placebo-controlled, dose-escalation phase I clinical study was conducted as follows: eligible participants were divided into 6 dose groups, among which 0.5 mg group was administrated with AK115 injection and the remaining 5 groups were randomly assigned to AK115 injection or accompanying placebo at a ratio of 3:1. Adverse events (AEs), PKs, PDs, and anti-drug antibodies (ADAs)/neutralizing antibody were monitored throughout the study.</p><p><strong>Results: </strong>A total of 42 participants completed the study. Twenty-seven (64.3%) participants occurred treatment emergent AEs (TEAEs), and 2 (4.80%) participants experienced treatment-related TEAEs. The TEAEs among the different dose groups were comparable. No significant differences were observed between the combined AK115 and the placebo group. It was demonstrated that the median T<sub>max</sub> was 4.50-14.0 days, the mean C<sub>max</sub> and AUC<sub>0-t</sub> of different doses groups were 30.8-5500 ng/mL and 792~181010 Day*ng/mL, respectively. The elimination half-life (t<sub>1/2</sub>) did not differ among the different dose groups and was calculated to be 7.60-17.7 days. In addition, the total NGF concentration and percentage change from baseline increased with an increase in the AK115 dose. No ADA positivity was detected in the healthy participants.</p><p><strong>Conclusion: </strong>The favorable safety and tolerability of AK115 in healthy Chinese participants, as well as the predictable PK and PD profiles, will provide sufficient support for future dose exploration studies of AK115 in patients with analgesia.</p><p><strong>Trial registration: </strong>This study was registered in the Chinese Clinical Trial Registry (CTR20220431) and the official website of the US Department of Health and Human Services, National Institutes of Health, with Clinical Trials. gov (NCT05286970) on March 2022.</p>","PeriodicalId":11290,"journal":{"name":"Drug Design, Development and Therapy","volume":"19 ","pages":"3225-3235"},"PeriodicalIF":4.7000,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037183/pdf/","citationCount":"0","resultStr":"{\"title\":\"The Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Subcutaneous Administration of a Novel Anti-NGF Monoclonal Antibody (AK115) in Healthy Participants: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Phase I Clinical Trial.\",\"authors\":\"Juan Zhang, Yu-Xin Fan, Yu Huang, Runfang Guan, Ruixia Li, Shuxian Long, Mei Yang, Binge Yu, Guo Qin Wang, Peng Chen, Xia Gong, Baiyong Li, Michelle Xia, Jianchang He\",\"doi\":\"10.2147/DDDT.S500902\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>This study aimed to investigate the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of a novel anti-nerve growth factor (NGF) monoclonal antibody (mAb) (AK115) in healthy Chinese participants.</p><p><strong>Methods: </strong>A randomized, double-blind, placebo-controlled, dose-escalation phase I clinical study was conducted as follows: eligible participants were divided into 6 dose groups, among which 0.5 mg group was administrated with AK115 injection and the remaining 5 groups were randomly assigned to AK115 injection or accompanying placebo at a ratio of 3:1. Adverse events (AEs), PKs, PDs, and anti-drug antibodies (ADAs)/neutralizing antibody were monitored throughout the study.</p><p><strong>Results: </strong>A total of 42 participants completed the study. Twenty-seven (64.3%) participants occurred treatment emergent AEs (TEAEs), and 2 (4.80%) participants experienced treatment-related TEAEs. The TEAEs among the different dose groups were comparable. No significant differences were observed between the combined AK115 and the placebo group. It was demonstrated that the median T<sub>max</sub> was 4.50-14.0 days, the mean C<sub>max</sub> and AUC<sub>0-t</sub> of different doses groups were 30.8-5500 ng/mL and 792~181010 Day*ng/mL, respectively. The elimination half-life (t<sub>1/2</sub>) did not differ among the different dose groups and was calculated to be 7.60-17.7 days. In addition, the total NGF concentration and percentage change from baseline increased with an increase in the AK115 dose. No ADA positivity was detected in the healthy participants.</p><p><strong>Conclusion: </strong>The favorable safety and tolerability of AK115 in healthy Chinese participants, as well as the predictable PK and PD profiles, will provide sufficient support for future dose exploration studies of AK115 in patients with analgesia.</p><p><strong>Trial registration: </strong>This study was registered in the Chinese Clinical Trial Registry (CTR20220431) and the official website of the US Department of Health and Human Services, National Institutes of Health, with Clinical Trials. gov (NCT05286970) on March 2022.</p>\",\"PeriodicalId\":11290,\"journal\":{\"name\":\"Drug Design, Development and Therapy\",\"volume\":\"19 \",\"pages\":\"3225-3235\"},\"PeriodicalIF\":4.7000,\"publicationDate\":\"2025-04-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037183/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Drug Design, Development and Therapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2147/DDDT.S500902\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"CHEMISTRY, MEDICINAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Drug Design, Development and Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2147/DDDT.S500902","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"CHEMISTRY, MEDICINAL","Score":null,"Total":0}
The Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single Subcutaneous Administration of a Novel Anti-NGF Monoclonal Antibody (AK115) in Healthy Participants: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation Phase I Clinical Trial.
Objective: This study aimed to investigate the safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of a novel anti-nerve growth factor (NGF) monoclonal antibody (mAb) (AK115) in healthy Chinese participants.
Methods: A randomized, double-blind, placebo-controlled, dose-escalation phase I clinical study was conducted as follows: eligible participants were divided into 6 dose groups, among which 0.5 mg group was administrated with AK115 injection and the remaining 5 groups were randomly assigned to AK115 injection or accompanying placebo at a ratio of 3:1. Adverse events (AEs), PKs, PDs, and anti-drug antibodies (ADAs)/neutralizing antibody were monitored throughout the study.
Results: A total of 42 participants completed the study. Twenty-seven (64.3%) participants occurred treatment emergent AEs (TEAEs), and 2 (4.80%) participants experienced treatment-related TEAEs. The TEAEs among the different dose groups were comparable. No significant differences were observed between the combined AK115 and the placebo group. It was demonstrated that the median Tmax was 4.50-14.0 days, the mean Cmax and AUC0-t of different doses groups were 30.8-5500 ng/mL and 792~181010 Day*ng/mL, respectively. The elimination half-life (t1/2) did not differ among the different dose groups and was calculated to be 7.60-17.7 days. In addition, the total NGF concentration and percentage change from baseline increased with an increase in the AK115 dose. No ADA positivity was detected in the healthy participants.
Conclusion: The favorable safety and tolerability of AK115 in healthy Chinese participants, as well as the predictable PK and PD profiles, will provide sufficient support for future dose exploration studies of AK115 in patients with analgesia.
Trial registration: This study was registered in the Chinese Clinical Trial Registry (CTR20220431) and the official website of the US Department of Health and Human Services, National Institutes of Health, with Clinical Trials. gov (NCT05286970) on March 2022.
期刊介绍：
Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications.
The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas.
Specific topics covered by the journal include:
Drug target identification and validation
Phenotypic screening and target deconvolution
Biochemical analyses of drug targets and their pathways
New methods or relevant applications in molecular/drug design and computer-aided drug discovery*
Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes)
Structural or molecular biological studies elucidating molecular recognition processes
Fragment-based drug discovery
Pharmaceutical/red biotechnology
Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products**
Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development
Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing)
Preclinical development studies
Translational animal models
Mechanisms of action and signalling pathways
Toxicology
Gene therapy, cell therapy and immunotherapy
Personalized medicine and pharmacogenomics
Clinical drug evaluation
Patient safety and sustained use of medicines.
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