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)
Trial Snapshot
- Phase
- Phase 1
- Status
- Recruiting
- Sponsor
- Monash University
- Enrollment
- 64
- Locations
- 3
- Primary Endpoint
- Incidence and Severity of Treatment-Emergent Adverse Events (TEAEs)
Study Overview
Brief Summary
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.
Detailed Description
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).
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 70 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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
Exclusion Criteria
- •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
Arms & Interventions
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.
Intervention: STX-1150 (Drug)
Outcomes
Primary Outcomes
Incidence and Severity of Treatment-Emergent Adverse Events (TEAEs)
Time Frame: Up to Week 52 from administration of STX-1150
Incidence and Severity of Serious Adverse Events (SAEs)
Time Frame: Up to Week 52 from administration of STX-1150
Incidence and Severity of Adverse Events of Special Interest (AESI)
Time Frame: Up to Week 52 from administration of STX-1150
Secondary Outcomes
- 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)
Investigators
Stephen Nicholls
Program Medical Director, Victorian Heart Hospital
Monash University