A Phase I/IIa,Open-label, Single Ascending Dose and Dose-expansion Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of YOLT-201 in Patients With Transthyretin Amyloidosis Polyneuropathy (ATTR-PN) or Transthyretin Amyloidosis Cardiomyopathy (ATTR-CM)
This study will be conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of YOLT-201 in participants with hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) and participants with hereditary transthyretin amyloidosis with cardiomyopathy (ATTRv-CM).
• Age 18 - 80 years old (including the critical values), regardless of gender;
• Body weight at the time of screening is between 40 - 90kg (including the critical values);
• TTR gene mutation is confirmed by genetic testing;
• At the time of screening, the following laboratory standards must be met:
∙ AST, ALT, and TBIL ≤ the upper limit of the normal value (ULN);
‣ For subjects with Gilbert syndrome, TBIL ≤ 2 times ULN;
‣ Glomerular filtration rate (GFR) ≥ 45 mL/min/1.73m2 (calculated according to the CKD-EPI formula);
‣ Platelet count ≥ 100 × 109/L;
‣ Partial thromboplastin time (APTT), prothrombin time (PT), and thrombin generation time (TGT) are all within the reference value range, fibrinogen (FIB) ≥ the lower limit of the normal value (LLN) and ≤ 1.5\*ULN, the international normalized ratio (INR) ≤ ULN, and if taking anticoagulant drugs, it is ≤ 2.5\*ULN;
‣ Vitamin A and vitamin B12 ≥ the lower limit of the reference value (LLN);
‣ Low-density lipoprotein cholesterol (LDL) \< 200 mg/dL (5.17 mmol/L).
• Drugs approved for the treatment of ATTR are not accessible (Criterion A) and/or the disease still progresses despite the use of drugs approved for the treatment of ATTR (Criterion B):
‣ Criterion A: Meeting one or more of the following criteria:
⁃ Drugs for the treatment of ATTR are not marketed in China;
• Unable to receive the approved drugs for ATTR treatment (e.g., intolerance or other medical, cost and/or other reasons);
⁃ Criterion B: Subjects have received ATTR drug treatment for at least 3 months, but the subject's condition has progressed as assessed by the investigator, and meets any of the following criteria:
• ATTR-CM: a. Increased number of hospitalizations related to heart failure; b. Worsening of NYHA classification; c. Decrease in KCCQ score by at least 5 points; d. Decrease in 6-MWT by at least 30m; e. Increase in NT-proBNP by 30%; f. Increase in Troponin I by 30%; g. Echocardiography indicates an increase in left ventricular wall thickness by 2mm; h. Echocardiography indicates a decrease in left ventricular ejection fraction by ≥ 5% or a decrease in global longitudinal strain by ≥ 1% or a decrease in stroke volume by ≥ 5%; i. New conduction block appears; ATTR-PN: a. PND score increase by ≥ 1 point; b. FAP increases by 1 stage; c. NIS score increase by ≥ 5 points; d. NIS-Lower Limb score increase by ≥ 5 points; e. mBMI decrease by ≥ 25 kg/m2×g/L; f. 10-MWT decrease by ≥ 0.1 m/s; g. Electroneurophysiological examination (electromyography) worsens compared to the previous.
• Agree to stop drinking alcohol within the screening period to 28 days after administration;
• Female subjects need to be menopausal (absence of menstruation for at least 1 year) or have undergone uterine/ovarian resection surgery; Male subjects and their partners have no fertility plans from the screening period to 6 months after the end of the trial and agree to take effective non-pharmaceutical contraceptive measures during the trial;
• The subject himself/herself (or his/her legally recognized representative) understands and signs the informed consent form;
• Agree not to receive other ATTR drug intervention treatment within at least 8 weeks after administration of YOLT-201;
• For ATTR-PN only:
⁃ Diagnosed as ATTR-PN according to the Consensus on the Diagnosis and Treatment of Transthyretin Amyloidosis Polyneuropathy, and the NIS score at the screening is ≥ 5 and ≤ 130, and the PND score is ≤ IIIb;
⁃ NT-proBNP \< 600pg/ml at the screening;
⁃ For ATTR-CM only:
⁃ Diagnosed as ATTR-CM according to the Expert Consensus on the Diagnosis and Treatment of Transthyretin Cardiac Amyloidosis;
⁃ The New York Heart Association (NYHA) cardiac function classification is grade II - III;
⁃ The 6-minute walk test (6-MWT) is ≥ 150 m at the screening;
⁃ NT-proBNP is ≥ 600pg/mL and ≤ 3000pg/mL at the screening;
⁃ At the screening, echocardiography suggests evidence of cardiac involvement: the thickness of the interventricular septum and/or the posterior wall of the left ventricle is ≥ 12 mm.