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)

Conditions: Transthyretin Amyloidosis Polyneuropathy; Transthyrexin Amyloidosis Cardiomyopathy

Summary: 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).


Eligibility criteria:
inclusion criteria: 1. age 18 - 80 years old (including the critical values), regardless of gender; 2. body weight at the time of screening is between 40 - 90kg (including the critical values); 3. ttr gene mutation is confirmed by genetic testing; 4. at the time of screening, the following laboratory standards must be met: 1. ast, alt, and tbil ≤ the upper limit of the normal value (uln); 2. for subjects with gilbert syndrome, tbil ≤ 2 times uln; 3. glomerular filtration rate (gfr) ≥ 45 ml/min/1.73m2 (calculated according to the ckd-epi formula); 4. platelet count ≥ 100 × 109/l; 5. 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; 6. vitamin a and vitamin b12 ≥ the lower limit of the reference value (lln); 7. low-density lipoprotein cholesterol (ldl) \< 200 mg/dl (5.17 mmol/l). 5. 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: 1. drugs for the treatment of attr are not marketed in china; 2. 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. 6. agree to stop drinking alcohol within the screening period to 28 days after administration; 7. 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; 8. the subject himself/herself (or his/her legally recognized representative) understands and signs the informed consent form; 9. agree not to receive other attr drug intervention treatment within at least 8 weeks after administration of yolt-201; for attr-pn only: 10. 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; 11. nt-probnp \< 600pg/ml at the screening; for attr-cm only: 12. diagnosed as attr-cm according to the "expert consensus on the diagnosis and treatment of transthyretin cardiac amyloidosis"; 13. the new york heart association (nyha) cardiac function classification is grade ii - iii; 14. the 6-minute walk test (6-mwt) is ≥ 150 m at the screening; 15. nt-probnp is ≥ 600pg/ml and ≤ 3000pg/ml at the screening; 16. 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. exclusion criteria: 1. amyloidosis is not caused by ttr protein, such as light chain amyloidosis; 2. there is meningeal transthyretin amyloidosis; 3. allergic to any lipid nanoparticle (lnp) component or has previously received lnp and experienced treatment-related laboratory abnormalities or adverse events; 4. use any of the following attr treatments within the prescribed time: * in the dose escalation stage of the first stage, the use history of patisiran, inotersen, and vutrisiran is excluded; * in the dose expansion stage of the second stage, the following are excluded: patisiran is used within 90 days before the administration of the investigational drug; inotersen is used within 160 days before the administration of the investigational drug; vutrisiran has a previous use history; * tafamidis: used within 10 days before the administration of the investigational drug; * diflunisal: used within 3 days before the administration of the investigational drug; * doxycycline and/or taurodeoxycholic acid: used within 14 days before the administration of the investigational drug; * previous use history of investigational gene editing drugs; * other drugs for the treatment of attr: the last use is less than 30 days or 5 half-lives before the administration of the investigational drug, whichever is longer. 5. unable or unwilling to supplement vitamin a during the trial; 6. history of multiple myeloma; 7. ophthalmological examination results at the screening are consistent with vitamin a deficiency; 8. abnormal thyroid function test with clinical significance judged by the investigator; 9. known or suspected systemic infection (viral, parasitic or fungal infection) within 14 days before screening; 10. history of past hepatitis b virus, hepatitis c virus, acquired immunodeficiency syndrome or positive hbsag, hcv-ab, and hiv-ab at the screening; 11. history of previous liver, heart or other organ transplantation or bone marrow transplantation or expected transplantation within 1 year (except for the history of corneal transplantation or planned corneal transplantation); 12. history of bleeding or coagulation disorders (such as cirrhosis, malignant hematological disease, antiphospholipid antibody syndrome); 13. history of acute thrombosis within 6 months before screening (such as acute myocardial infarction, acute cerebral infarction), or positive leiden factor v and/or prothrombin gene test; 14. history of malignant tumor within 5 years before screening (except for basal cell carcinoma of the skin, radicalized squamous cell carcinoma of the skin, and carcinoma in situ of the cervix); 15. planned invasive cardiovascular surgery during the trial (such as coronary artery stent/coronary artery bypass, pacemaker placement, etc.); those who have undergone cardiovascular invasive surgery within 90 days before screening or have been hospitalized due to heart failure; 16. history of alcohol abuse within 3 years before screening (definition of alcohol abuse: women drink ≥ 4 glasses/day or 8 glasses/week, men ≥ 5 glasses or 15 glasses/week, where 1 glass = 14g of pure alcohol); 17. expected survival period is less than 1 year; 18. other situations that the investigator deems inappropriate to enter this trial; for attr-pn only: 19. other known diseases that cause motor or sensory neuropathy (such as diabetic neuropathy, neuropathy related to autoimmune diseases, etc.); 20. diagnosed with type 1 diabetes or type 2 diabetes for ≥ 5 years; 21. nyha cardiac function classification is grade iii or iv within 90 days before screening; for attr-cm only: 22. nyha cardiac function classification is grade iv within 90 days before screening; 23. pnd score is grade iiia, iiib or iv at the screening; 24. suffering from other cardiomyopathies not caused by ttr (such as hypertensive cardiomyopathy, valvular heart disease, cardiomyopathy caused by ischemic heart disease, etc.).