Nerve Growth Factor Encapsulated With 2-methacryloyloxyethyl Phosphorylcholine Nanocapsules in the Treatment of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is one of the most lethal neurodegenerative diseases. Most patients die due to respiratory failure 3-5 years after disease onset. Due to the low permeability and blocking of the blood-brain barrier (BBB) on more than 95% of all kinds of drugs, the drug treatment of ALS is relatively limited. Although a series of studies have been carried out on new therapies to ALS, such as monoclonal antibodies represented by ozanezumab and antisense oligonucleotides represented by tofersen, the conclusions are mostly limited to safety evaluation.

Nerve growth factor (NGF) provides protection and/or regeneration for neurons in the peripheral and central nervous system (CNS), which is considered to be a nerve regeneration agent with great therapeutic potential. The phase I clinical trial of intravenous recombinant human nerve growth factor (rhNGF) showed that, on the premise of ensuring safety, only a trace of NGF (3.6-7.38 ng/ml within 5 minutes) was detected in the plasma samples of the subjects who were injected with rhNGF 1.0 μg/kg (the maximum dose of this trial design).

In purpose of improving the therapeutic effect of NGF, the investigators plan to encapsulate NGF in nanoparticles linked by 2-methacryloyloxyethyl phosphorylcholine (MPC), consisting of one molecule of choline and one molecule of acetylcholine analog. After intravenous administration, the drug particles are effectively delivered to the CNS via receptor-mediated transcytosis (RMT) with the help of acetylcholine transporter and choline transporter widely expressed on brain capillary endothelial cells. The animal experiments have confirmed that intravenous injection of MPC encapsulated NGF capsule \[n(NGF)\] can effectively prolong the survival time of SOD1G93A mice, reduce the body weight loss and delay the time of dyskinesia onset compared with NGF. Similar results were obtained in the rhesus monkey model.

The purpose of this study is to explore the efficacy and safety of NGF encapsulated with MPC nanocapsules in the treatment of ALS patients.

This is a prospective, randomized, open-label, blinded endpoint (PROBE) clinical trial. The trial planned to enroll 60 ALS patients, aged 18-80 years, with disease duration 6 months to 3 years, with forced vital capacity (FVC) ≥ 85% of predicted value.

Patients will be randomly assigned to one of the following 3 groups at 1:1 ratio.

Treatment group 1: NGF 60ml wrapped in MPC nanomaterials (dose was given as 320 μg/ml) was injected intravenously every week for 12 weeks, including one administration at the starting point for a total of 13 times, as well as maintaining original basic drugs and rehabilitation treatment.

Treatment group 2: NGF 37ml wrapped in MPC nanomaterials (dose was given as 320 μg/ml) was injected intravenously every week for 12 weeks, including one administration at the starting point for a total of 13 times, as well as maintaining original basic drugs and rehabilitation treatment.

Control group: NGF 60ml (dose was given as 320 μg/ml) was injected intravenously every week for 12 weeks, including one administration at the starting point for a total of 13 times, as well as maintaining original basic drugs and rehabilitation treatment.

Face to face interviews will be made on baseline, 28±4 days after randomization, 84±7 days after randomization and 120±7 days after randomization. Online interviews will be made on 180±14 days and 1 year ±14 days after randomization.

The primary outcome, Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) scores of ALS patients in the treatment group and the control group after 3 months of NGF injection, will be compared by Wilcoxon rank sum test, and β and 95% confidence interval (CI) will be calculated. The survival / mortality of ALS patients in treatment group and control group will be analyzed by COX regression model, and hazard ratio (HR) value and 95%CI were be calculated. Survival curve will be calculated by Nelson-Aalen cumulative risk curve, and Gray's test will be used for comparison between groups.

• Endpoint events [Срок оценки: 28±4 days, 84±7 days, 120±7 days, 180±14 days, 1 year ±14 days]
• Tolerance [Срок оценки: 28±4 days, 84±7 days]
• Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) [Срок оценки: 28±4 days, 120±7 days, 180±14 days, 1 year ±14 days]
• Lung function: forced vital capacity [Срок оценки: 28±4 days, 84±7 days, 120±7 days]
• Lung function: slow vital capacity [Срок оценки: 28±4 days, 84±7 days, 120±7 days]
• Lung function: transcutaneous oxygen saturation [Срок оценки: 28±4 days, 84±7 days, 120±7 days]
• Muscle involvement [Срок оценки: 120±7 days]