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Safety, Tolerability, Pharmacokinetics, and Immunogenicity of a Novel Recombination Human Nerve Growth Factor in Healthy Chinese Subjects

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Abstract

Background

Nerve growth factor (NGF), the first-discovered member of the neurotrophin family, has long been regarded as a potential drug to combat acute and chronic neurodegenerative processes. However, the pharmacokinetic profile of NGF is poorly described.

Objectives

The aim of this study was to investigate the safety, tolerability, pharmacokinetics, and immunogenicity of a novel recombinant human NGF (rhNGF) in healthy Chinese subjects.

Method

The study randomized 48 and 36 subjects to receive (i) single-ascending dose (SAD group; 7.5, 15, 30, 45, 60, 75 μg or placebo) and (ii) multiple-ascending dose (MAD group; 15, 30, 45 μg, or placebo) rhNGF intramuscular injections, respectively. In the SAD group, all participants received rhNGF or placebo only once. In the MAD group, participants were randomly assigned to receive multiple doses of rhNGF or placebo once a day for 7 consecutive days. Adverse events (AEs) and anti-drug antibodies (ADAs) were monitored throughout the study. Recombinant human NGF serum concentrations were determined using a highly sensitive enzyme-linked immunosorbent assay.

Results

All AEs were mild, except for some injection-site pain and fibromyalgia, which were experienced as moderate AEs. Only one moderate AE was observed in the 15 μg cohort throughout the study and resolved within 24 hours of stopping dosing. Many participants (10% in 30 μg, 50% in 45 μg, and 50% in 60 μg in the SAD group; 10% in 15 μg, 30% in 30 μg, and 30% in 45 μg in the MAD group) experienced moderate fibromyalgia. However, all moderate fibromyalgia were resolved by the end of the subject’s participation in the study. No severe AEs or clinically significant abnormalities were reported. All subjects in the 75 μg cohort experienced positive ADA in the SAD group, and one subject in the 30 μg dose and four subjects in the 45 μg dose also experienced positive ADA in the MAD group. Recombinant human nerve growth factor was absorbed (median Tmax, 4.0–5.3 h) and eliminated biexponentially (mean t1/2, 4.53–6.09 h) with a moderate speed. The Cmax and AUC increased in an approximately dose-proportional manner over the dose range of 7.5–45 μg, and at doses higher than 45 μg these parameters increased more than dose proportionally. There was no obvious accumulation after 7 days of daily dosing of rhNGF.

Conclusion

The favorable safety and tolerability and predictable pharmacokinetic profile of rhNGF in healthy Chinese subjects support its continuing clinical development for the treatment of nerve injury and neurodegenerative diseases. The AEs and immunogenicity of rhNGF will continue to be monitored in future clinical trials.

Trial Registration

This study was registered with Chinadrugtrials.org.cn (ChiCTR2100042094) on January 13th, 2021.

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Acknowledgements

We would like to express our gratitude to the study participants, their families, and the staff at the study site. We thank the clinical study team from the Clinical Trial Center/NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug of West China Hospital of Sichuan University (Chengdu, China) for their support in study execution, study design, data acquisition, statistical analyses, and manuscript revisions.

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Authors and Affiliations

  1. Clinical Trial Center/NMPA Key Laboratory for Clinical Research and Evaluation of Innovative Drug, West China Hospital of Sichuan University, Telecom Road, Wuhou District, Chengdu, 610041, China

    Qi Shen, Mengyu Zhang, Ying Jin, Xiangjie Di, Runhan Liu & Zhenlei Wang

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  1. Qi Shen
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Correspondence to Zhenlei Wang.

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Funding

This research was supported by the Youth Program of National Natural Science Foundation of China (81903722).

Conflict of interest/competing interest

West China Hospital of Sichuan University has received research funds from Sichuan Pride Times Pharmaceutical Co., Ltd. (Chengdu, China). The authors are not employees of the sponsor and declare that there are no other potential conflicts of interest.

Ethics approval

This study was approved by the Ethics Committee of the West China Hospital of Sichuan University (Ethics approval number: 2020CT(WM)38; Chengdu, China) and performed in accordance with the Declaration of Helsinki and ICH-GCP guidelines.

Consent to participate

All participants provided informed consent before undergoing any study-specific procedures.

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Not applicable.

Availability of data and materials

Data are available from the corresponding author on reasonable request.

Code availability

Not applicable.

Author contributions

The manuscript was developed under the primary guidance of QS and ZW. Material preparation, data collection, and analysis were performed by MZ, YJ, XD, RL, and ZW. All authors reviewed and provided comments on the manuscript. All authors read and approved the final manuscript.

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Shen, Q., Zhang, M., Jin, Y. et al. Safety, Tolerability, Pharmacokinetics, and Immunogenicity of a Novel Recombination Human Nerve Growth Factor in Healthy Chinese Subjects. CNS Drugs 37, 231–242 (2023). https://doi.org/10.1007/s40263-023-00991-z

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