A Phase 1 Open-Label Single Ascending Dose (Part 1) and Single or Multi-Dose Expansion (Part 2) Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of STX-1150 in Participants With Elevated Low-Density Lipoprotein Cholesterol (LDL-C)
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 64
- 试验地点
- 2
- 主要终点
- Incidence and Severity of Treatment-Emergent Adverse Events (TEAEs)
研究概览
简要总结
STX-1150 is an investigational therapy designed to lower LDL-C by silencing a gene called PCSK9 in the liver. STX-1150 does not edit or permanently change the gene. STX-1150 comprises an mRNA and guide RNA (gRNA) delivered via lipid nanoparticles (LNP) for intravenous infusion. The mRNA produces a protein that switches off the PCSK9 gene expression without altering the DNA sequence. This process leverages natural mechanisms that regulate gene activity.
The study will enroll up to 64 participants with elevated LDL-C across sites in Australia and New Zealand. The follow-up period will be up to 1- year post-treatment.
详细描述
STX-1150 is an investigational product designed to epigenetically silence the PCSK9 gene. It comprises an mRNA and a guide RNA (gRNA) delivered in a lipid nanoparticle (LNP) for intravenous (IV) infusion.
STX-1150 epigenetically silences the expression of the PCSK9 gene in the liver, thereby reducing circulating PCSK9 and LDL-C levels. The active components, an mRNA and a gRNA are encapsulated in lipid nanoparticles (LNPs) for targeted hepatic delivery. The gRNA precisely guides the complex to a specific locus within the PCSK9 gene promoter.
By reducing PCSK9 expression, STX-1150 prevents the degradation of LDL receptors (LDL-R), leading to increased LDL-R levels on hepatocytes and enhanced clearance of LDL-C from the bloodstream. This targeted and durable epigenetic silencing represents a promising therapeutic strategy for long-term LDL-C reduction, particularly benefiting patients with elevated LDL-C or a high risk for Atherosclerotic Cardiovascular Disease (ASCVD).
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Elevated serum LDL-C with or without LDL-C lowering medication
- •Willing and able to give informed consent before initiation of any study-related procedures and willing to comply with all required study procedures
排除标准
- •Patients with history of an ASCVD event </= 6 months.
- •Any uncontrolled or serious disease, or any medical or surgical condition that may interfere with participation
- •Diagnosis of familial hypercholesterolemia
- •Active or history of liver disease
- •Previous treatment with PCSK9-inhibitor or other prior treatment within a specified timeframe
- •Clinically significant abnormal laboratory values
研究组 & 干预措施
Arm 1
Part 1: An open-label, single ascending dose will serve to identify the Dose-Limiting Toxicities (DLTs) and Optimal Biological Dose (OBD) of STX-1150.
Part 2: Following Part 1, an open-label, single or multi-dose expansion of the OBD cohort will be conducted to further characterize the effect of STX-1150 and obtain additional safety data at the OBD.
干预措施: STX-1150 (Drug)
结局指标
主要结局
Incidence and Severity of Treatment-Emergent Adverse Events (TEAEs)
时间窗: Up to Week 52 from administration of STX-1150
Incidence and Severity of Serious Adverse Events (SAEs)
时间窗: Up to Week 52 from administration of STX-1150
Incidence and Severity of Adverse Events of Special Interest (AESI)
时间窗: Up to Week 52 from administration of STX-1150
Incidence and severity of treatment-emergent adverse events (TEAEs)
时间窗: up to Week 52 from administration of STX-1150
Events occurring after administration of STX-1150 or that are preexisting and worsen in severity or become serious after administration of study drug are considered TEAEs. The investigator will make an assessment of severity for each TEAEs reported during the clinical study based on the CTCAE
Incidence and severity of serious adverse events (SAEs)
时间窗: up to Week 52 from administration of STX-1150
A SAE is defined as any untoward medical occurrence that, at any dose: * Results in death * Is life-threatening. * Requires inpatient hospitalisation or prolongation of existing hospitalisation * Results in persistent disability/incapacity * Is a congenital anomaly/birth defect * Is an important medical event The investigator will make an assessment of severity for each SAE reported during the clinical study based on the CTCAE
Incidence and severity of adverse events of special interest (AESI)
时间窗: up to Week 52 from administration of STX-1150
The following cardiovascular (CV) events will be defined as adverse events of special interest (AESI): CV death, non-fatal myocardial infarction (MI), major coronary events (coronary heart disease death, resuscitated cardiac arrest, non-fatal MI), ischemic stroke, and hemorrhagic stroke, and IRR grade 3 or higher (per CTCAE) associated with the administration of STX-1150. The investigator will make an assessment of severity for each AESI reported during the clinical study based on the CTCAE.
次要结局
- Incidence of dose-limiting toxicities (DLTs)(Within 14 days from administration of STX-1150)
- Percent Change from Baseline in Plasma PCSK9 Concentration(Up to Week 52)
- Percent Change from Baseline in LDL-C(Up to 52 weeks)
- Plasma Concentrations of STX-1150 Lipid Components(Up to 52 weeks)
- Number of Participants with Treatment-Induced Immunogenicity(Up to 52 Weeks)
- Absolute Change from Baseline in LDL-C(Up to 52 weeks)
- The Absolute Change from Baseline in Plasma PCSK9 Concentration(Up to Week 52)
- Number of participants with treatment-induced immunogenicity(Up to 52 weeks)
- Incidence of dose-limiting toxicities (DLTs)(within 14 days from administration of STX-1150)
- Percent of change from baseline in plasma PCSK9 concentration(up to Week 52)
- Percent change from baseline in LDL-C(Up to 52 weeks)
- Plasma concentrations of STX-1150 lipid components(Up to 52 weeks)
- Absolute change from baseline in LDL-C(Up to 52 weeks)
- The absolute change from baseline in plasma PCSK9 concentration(up to Week 52)
研究者
Stephen Nicholls
Program Medical Director, Victorian Heart Hospital
Monash University