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

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.