safety and tolerance of rag-17 in amyotrophic lateral sclerosis patients with sod1 gene mutation

Conditions: Gene Mutation

Summary: the goal of this clinical trial is to evaluate the safety, tolerability and pharmacokinetics of rag-17 in adult amyotrophic lateral sclerosis (als) patients with sod1 mutation. patients will receive drug treamtent via dose escalation which ranging from minimum of 60 mg to the maximum tolerated dose (mtd), after reaching the tolerated dose, a fixed dose of the drug is given once every two months for continuous treatment, and the total treatment cycle is 8 months. the duration of this study is two years.

this study is an open-label, single center, first-in-human dose escalation study to evaluate the safety, tolerability and pharmacokinetics of rag-17 in adultamyotrophic lateral sclerosis (als) patients with sod1 mutation via dose escalations. patients will receive 60mg of rag-17 firstly, within 14 days after the first administration, the subject has no adverse event (ae) and serious adverse event (sae), the subject can accept dose escalation every 30mg/14 days of observation period. 3 to 4 dose escalations are planned to reach the dose limiting toxicity (dlt), with optimal doses for continual 6-month treatment cycles. for the dose of subsequent continuous treatment, an optimal dose between the safe dose and the maximum tolerated dose (mtd) is selected as the continuous treatment dose. sas software is used for safety analysis. the sample size of this study is 6 als patients with sod1 mutation.

Eligibility criteria:
inclusion criteria: * patients who are judged by professional medical staff to still be able to carry out the clinical trial project cycle; * 18 years old ≤ age ≤ 75 years old, males or females; * als patients with confirmed sod1 gene mutations document (known sod1 mutation sites and related disease progression have been reported); * forced vital capacity ≥ 50% of predicted vital capacity during the screening period; * diagnosis of confirmed or probable familial or sporadic als in accordance with the revised ei escorial diagnostic criteria for amyotrophic lateral sclerosis of the world federation of neurology; * the patient or patient's legal representative clearly understands and voluntarily participates in the study and signs the informed consent form; * subjects (including male subjects) are willing to have no birth plan and voluntarily take effective contraceptive measures during the entire study period and within 3 months after the end of the study, and have no plan to donate sperm or eggs. exclusion criteria: * patients with sod1 mutations occurring at nucleotides 44 to 66 (calculated from the start of sod1 protein translation), patients with p.f21c mutation; * patients who have previously received or are currently receiving tofersen treatment; * hiv test positive or history of positive tests; * positive hepatitis c virus antibody or history of positive tests; * active hepatitis b infection (positive hepatitis b surface antigen and/or positive hepatitis b core antibody); * have used other investigational drugs within 1 month or within 5 drug half-lives; * diseases and deformities of the lumbar spine; * have other conditions known to be associated with motor neuron dysfunction that may confuse or obscure an als diagnosis; * other psychiatric disorders diagnosed according to dsm-v diagnostic criteria, or significant suicide intent; * with severe hepatic insufficiency, renal insufficiency or severe cardiac insufficiency (severe hepatic insufficiency refers to alt value≥2.0 times the upper limit of normal value or ast value≥2.0 times the upper limit of normal value; severe renal insufficiency refers to cre≥1.5 times the upper limit of normal value or egfr\<40ml/min/1.73m2; severe cardiac insufficiency refers to nyha class 3-4); * permanently dependent on ventilator-assisted ventilation; * history of alcohol and drug abuse; * patients who are pregnant, breast-feeding, or who are likely to become pregnant and plan to become pregnant; * patients participating in other clinical trials or using other biological agents, drugs or devices under investigation; * patients who have received any vaccinations within 28 days; * contraindications to mri (eg, claustrophobia); * unable to be cooperative and complete the follow-up due to other reasons.

Keywords: rag-17 sod1 gene mutation amyotrophic lateral sclerosis