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).

Study Overview

• Status: Recruiting
• Conditions: Transthyretin Amyloidosis Polyneuropathy; Transthyrexin Amyloidosis Cardiomyopathy
• Intervention / Treatment: Drug: YOLT-201

• Study Type: Interventional
• Enrollment (Estimated): 31
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100000
      • Recruiting
      • Peking Union Medical College Hospital
      • Contact: Shuyang Zhang; Phone Number: 010 69155068; Email: shuyangzhang103@163.com
  • Hunan
    • Changsha, Hunan, China, 410000
      • Recruiting
      • The second Xiangya hospital of central south university
      • Contact: Daoquan Peng; Phone Number: 0731 85295407; Email: pengdq@hotmail.com
  • Zhejiang
    • Hanzhou, Zhejiang, China, 310000
      • Recruiting
      • the First Affiliated Hospital, School of Medicine, Zhejiang University
      • Contact: Tingbo Liang; Phone Number: 0571 87236560; Email: liangtingbo@zju.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: YOLT-201	Drug: YOLT-201; Infusion of YOLT-201 at Day 1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability	Incidence and severity of adverse events (AEs) and serious adverse events (SAEs)	through week 104

Collaborators and Investigators

• Sponsor: YolTech Therapeutics Co., Ltd

Study record dates

Study Major Dates

• Study Start (Actual): May 23, 2024
• Primary Completion (Estimated): June 30, 2025
• Study Completion (Estimated): June 30, 2026

Study Registration Dates

• First Submitted: August 1, 2024
• First Submitted That Met QC Criteria: August 1, 2024
• First Posted (Actual): August 6, 2024

Study Record Updates

• Last Update Posted (Actual): August 6, 2024
• Last Update Submitted That Met QC Criteria: August 1, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Metabolic Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Neuromuscular Diseases; Neurodegenerative Diseases; Peripheral Nervous System Diseases; Proteostasis Deficiencies; Metabolism, Inborn Errors; Heredodegenerative Disorders, Nervous System; Amyloidosis, Familial; Amyloidosis; Cardiomyopathies; Polyneuropathies; Amyloid Neuropathies; Amyloid Neuropathies, Familial
• Other Study ID Numbers: YT-YOLT-201-101

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No