Efficacy and Safety of Intravenous YOLT-201 for Transthyretin Amyloidosis Cardiomyopathy

Study Overview
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Brief Summary
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This study is a single-arm, open-label, dose-escalation trial aimed at determining the optimal biologically active dose (OBD) of YOLT-201 and providing safety and efficacy evaluation. The OBD is the dose at which serum transthyretin (TTR) protein baseline reduction is ≥60% but not exceeding 95% after 28 days of dosing. The OBD dose should not exceed the maximum tolerated dose (MTD), defined as the highest dose at which no more than one subject experiences dose-limiting toxicity (DLT) within each cohort.

Official Title
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Efficacy and Safety of Intravenous YOLT-201 for Transthyretin Amyloidosis Cardiomyopathy

Conditions
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Transthyroxin Amyloidosis Cardiomyopathy

Intervention / Treatment
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* Drug: YOLT-201


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects, aged 18 to 80 years. Diagnosed with transthyretin amyloid cardiomyopathy (ATTR-CM) according to the Expert Consensus on Diagnosis and Treatment of Transthyretin Protein Cardiac Amyloidosis, including both hereditary (ATTRm) and wild-type (ATTRwt) types; and meeting the following criteria: 2.1. New York Heart Association (NYHA) functional class I-III. 2.2. Six-minute walk test distance ≥150 m at screening. 2.3. NT-proBNP level ≥300 pg/mL at screening. 2.4. Evidence of cardiac involvement on echocardiography: left ventricular wall thickness ≥12 mm in diastole. Body weight must be between 50 and 90 kg at baseline. Subjects must meet the following laboratory criteria at screening: 4.1. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (excluding Gilbert's syndrome), and international normalized ratio (INR) within the normal upper limit range. 4.2 For subjects with a history of Gilbert's syndrome, total bilirubin <2 × ULN. 4.3 Estimated glomerular filtration rate (GFR) >45 mL/min/1.73 m2 based on the Modification of Diet in Renal Disease equation adjusted for diet at screening. 4.4 Platelet count ≥100 x 109/L. 4.5 Activated partial thromboplastin time (aPTT), prothrombin time (PT), thrombin generation time (TGT), fibrinogen, and d-dimer within normal levels. 4.6 N-terminal pro-brain natriuretic peptide (NT-proBNP) <8500 pg/mL. 4.7 Low-density lipoprotein (LDL) cholesterol <200 mg/dL. 4.8 Vitamin A > lower limit of normal (LLN). 4.9 Thyroid-stimulating hormone (TSH) within the normal range. 4.10 Vitamin B12 level ≥ LLN. Must voluntarily abstain from alcohol starting from the time of screening. Lack of approved treatment for ATTR-CM (Criterion A) or progressive disease despite ATTR-CM treatment (Criterion B). Criterion A: Lack of approved treatment for ATTR-CM: ATTR-CM-directed therapy is not approved in the region where the subject resides. The subject cannot receive approved ATTR-CM treatment due to intolerance or other medical, economic, and/or other reasons. Criterion B: Assessment by investigator of symptomatic progression in ATTR-CM for at least 6 months and meeting all the following criteria: Increase in Cardiac Neuropathy Disability score >1 point. Increase in Familial Amyloid Polyneuropathy Disease stage >1 point. NIS score >5 points. Body mass index (BMI) >25 kg/m2×g/L. Decrease in six-minute walk test distance by 30 meters. Decrease in 10-meter walk test speed by 20.1 meters/second. Note: Subjects with a history of receiving TTR-lowering treatments (patisiran, inotersen) will be excluded. Female subjects must be postmenopausal: Postmenopausal is defined as the absence of menstruation for at least 1 year prior to screening without any other medical reasons. Male subjects with reproductive potential or their female partners planning to conceive must use contraception consistently from screening through 84 days after drug administration. Male subjects must agree not to donate sperm for at least 84 days after drug administration. Subjects must agree not to participate in any other interventional study for at least 28 days after administration of YOLT-201. Ability to provide signed informed consent. No exclusion criteria can be waived. Exclusion Criteria: Non-TTR protein amyloidosis, such as immunoglobulin light chain (AL) amyloidosis. Cerebral amyloid angiopathy. Allergy to any component of lipid nanoparticle (LNP) or previous exposure to LNP components with associated laboratory abnormalities or adverse reactions: 3.1 Baseline ALT or AST >3× ULN or an increase of 3 times the baseline value after receiving an LNP product. 3.2 Baseline INR, aPTT, or d-dimer >1.5× ULN; if the baseline is already above normal, then 1.5 times the baseline value. 3.3 Any adverse reaction related to LNP treatment is defined as Grade 3 or higher (CTCAE). Injection site-related reactions (IRR) require treatment or discontinuation of the infusion, slowing down the infusion rate to mitigate infusion-related reactions. The investigator deems any adverse events related to LNP treatment should be excluded. Use of any directed therapy for ATTR within the specified timeframe: 4.1 Patisiran (LNP small interfering RNA siRNA) treatment product. 4.1.1 Part 1: Treatment history. 4.1.2 Part 2: The last dose was received within 90 days prior to this study cycle. 4.2 Inotersen (antisense oligonucleotide ASO). 4.2.1 Treatment history. 4.2.2 The last dose was received within 160 days prior to this study cycle. 4.3 Vutrisiran (investigational siRNA therapeutic GalNAc conjugate) previous treatment history. 4.4 Tafamidis (TTR stabilizer): The last dose was received less than 14 days prior to the study drug administration. 4.5 Diflunisal (TTR stabilizer): The last dose was received less than 3 days prior to study drug administration. 4.5.1 Streptomycin and/or/taurodeoxycholic acid (TTR matrix solvent): Last dose received less than 14 days prior to study drug administration. 4.5.2 Any other medication used to treat ATTR-CM: Last dose received less than 30 days or 5 half-lives (whichever is longer) prior to study drug administration. Sensory, motor, or autonomic neuropathy caused by other known underlying conditions (such as diabetic neuropathy, autoimmune-related neuropathy, etc.). Type I diabetes or diagnosed with type II diabetes for more than 5 years. Current or previous New York Heart Association (NYHA) class IV symptoms at screening or within 90 days prior to screening or worsening heart failure symptoms. Cardiovascular hospitalization or invasive cardiac procedure within 90 days prior to screening or during screening. Anticipated invasive cardiovascular procedures (such as coronary artery stenting, pacemaker implantation, etc.) within 28 days after drug administration. Inability or unwillingness to supplement with vitamin A. Inability or unwillingness to adhere to the required medication treatment regimen prior to study initiation. Use antiplatelet agents (such as aspirin clopidogrel) or anticoagulant therapy (such as warfarin, dabigatran, and apixaban) within 14 days prior to initiation of study medication. History of thrombophilia or positive mutation testing for factor V Leiden and prothrombin. Investigator's assessment that the expected survival is less than 2 years. Ophthalmological examination findings were consistent with vitamin A deficiency. History of liver cirrhosis. Known or suspected systemic viral, parasitic, or fungal infection or antibiotic treatment for bacterial infection within 14 days after screening. History of hepatitis B, hepatitis C infection, positive hepatitis B surface antigen (HBsAg), or hepatitis C virus antibody (HCV Ab) at screening. History of human immunodeficiency virus (HIV) positivity. Solid organ transplantation (liver, heart, other organs), bone marrow transplantation within 1 year prior to screening, or planned transplantation. Note: No history of corneal transplantation or planned corneal transplantation. Active malignancy within 5 years prior to screening, excluding basal cell carcinoma of the skin, adequately treated squamous cell carcinoma of the skin, adequately treated cervical carcinoma, or low-grade prostate carcinoma under active surveillance. History of alcohol abuse or substance abuse within 3 years prior to screening. Women of childbearing potential or currently breastfeeding. Investigator's judgment that any condition, laboratory abnormality, or other reason could potentially harm the subject's safety, compromise the assessment of study results, or hinder the subject's compliance with the study. Refrain from complying with study procedures, including required follow-up visits, or unwillingness to cooperate with the investigator fully. No exclusion criteria can be waived or ignored.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: YOLT-201<br>Phase 1a, which includes three dose cohorts (0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg) with a sample size of 1-2 subjects per cohort, aims to determine the optimal biologically active dose (OBD) of YOLT-201. Phase 1b will enroll an additional 8 subjects at the OBD to evaluate its safety and preliminary efficacy further | Drug: YOLT-201<br>* Infusion of YOLT-201 at Day 1。<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse event Adverse event Adverse events | Adverse events | hrough study completion, an average of 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | Cmax | hrough study completion, an average of 1 year | 
| Tmax | Tmax | hrough study completion, an average of 1 year | 
| AUCinf | AUCinf | hrough study completion, an average of 1 year | 
| AUClast | AUClast | through study completion, an average of 1 year | 
| t1/2 | t1/2 | through study completion, an average of 1 year | 
| CL/F | CL/F | through study completion, an average of 1 year | 
| change of TTR | change of TTR | through study completion, an average of 1 year | 
| change of NIS | change of NIS | Week 4，Week 52 | 
| change of QOL-DN | change of QOL-DN | Week 4、Week 36、Week 52 | 
| change of EQ-5D-5L | change of EQ-5D-5L | Week 36、Week 52 | 
| change of 10-MWT | change of 10-MWT | Week 36、Week 52 | 
| change of NFL | change of NFL | Week 4、Week 36、Week 52 | 
| change of mBMI | change of mBMI | Week 4、Week 36、Week 52 | 
| change of NT-proBNP | NT-proBNP | Week 24、Week 36、Week 52 | 
| change of troponin | change of troponin | Week 24、Week 36、Week 52 | 
| change of 6-MWT | change of 6-MWT | Week 36、Week 52 | 
| change of NYHA cardiac function classification change of NYHA cardiac function classification | change of NYHA cardiac function classification NYHA cardiac function classification change of NYHA cardiac function classification | Week 24、Week 36、Week 52 | 
| change of KCCQ | change of KCCQ | Week 24、Week 36、Week 52 | 
| change of Interventricular septal wall thickness | change of Interventricular septal wall thickness on echocardiography | Week 52 | 
| change of Left ventricular (LV) posterior wall thickness | change of Left ventricular (LV) posterior wall thickness on echocardiography | Week 52 | 
| change of LV mass | change of LV mass on echocardiography | Week 52 | 
| change of LV end-diastolic volume | change of LV end-diastolic volume on echocardiography | Week 52 | 
| change of LV end-systolic volume | change of LV end-systolic volume on echocardiography | Week 52 | 
| change of LV ejection fraction | change of LV ejection fraction on echocardiography | Week 52 | 
| change of Cardiac output | change of Cardiac output on echocardiography | Week 52 | 
| change of Global longitudinal strain | change of Global longitudinal strain on echocardiography | Week 52 | 
| change of Left atrial size | change of Left atrial size on echocardiography | Week 52 | 
| change of Left ventricular end-diastolic volume on Cardiac magnetic resonance | change of Left ventricular end-diastolic volume on Cardiac magnetic resonance | W52 | 
| change of Left ventricular end-systolic volume on Cardiac magnetic resonance | change of Left ventricular end-systolic volume on Cardiac magnetic resonance | Week 52 | 
| change of Left ventricular systolic volume on Cardiac magnetic resonance | change of Left ventricular systolic volume on Cardiac magnetic resonance | Week 52 | 
| change of Left ventricular ejection fraction on Cardiac magnetic resonance | change of Left ventricular ejection fraction on Cardiac magnetic resonance | Week 52 | 
| change of Overall longitudinal strain of left ventricle on Cardiac magnetic resonance | change of Overall longitudinal strain of left ventricle on Cardiac magnetic resonance | Week 52 | 
| change of Mitral ring plane contraction displacement on Cardiac magnetic resonance | change of Mitral ring plane contraction displacement on Cardiac magnetic resonance | Week 52 | 
| change of Left ventricular myocardial mass on Cardiac magnetic resonance | change of Left ventricular myocardial mass on Cardiac magnetic resonance | Week 52 | 
| change of Right ventricular end-diastolic volume on Cardiac magnetic resonance | change of Right ventricular end-diastolic volume on Cardiac magnetic resonance | Week 52 | 
| change of Right ventricular end-systolic volume on Cardiac magnetic resonance | change of Right ventricular end-systolic volume on Cardiac magnetic resonance | Week 52 | 
| change of Right ventricular systolic volume on Cardiac magnetic resonance | change of Right ventricular systolic volume on Cardiac magnetic resonance | Week 52 | 
| change of Right ventricular ejection fraction on Cardiac magnetic resonance | change of Right ventricular ejection fraction on Cardiac magnetic resonance | Week 52 | 
| change of Tricuspid ring plane contraction offset on Cardiac magnetic resonance | change of Tricuspid ring plane contraction offset on Cardiac magnetic resonance | Week 52 | 
| change of Right ventricular longitudinal strain on Cardiac magnetic resonance | change of Right ventricular longitudinal strain on Cardiac magnetic resonance | Week 52 | 
| change of Left atrial volume on Cardiac magnetic resonance | change of Left atrial volume on Cardiac magnetic resonance | Week 52 | 
| change of Right atrial volume on Cardiac magnetic resonance | change of Right atrial volume on Cardiac magnetic resonance | Week 52 | 
| change of Extracellular volume on Cardiac magnetic resonance | change of Extracellular volume on Cardiac magnetic resonance | Week 52 | 
| level of anti-drug antibody | level of anti-drug antibody | through study completion, an average of 1 year | 
| level of cas9 antibody | level of cas9 antibody | through study completion, an average of 1 year |