Elevated Lipoprotein(a)
Conditions
Keywords
SAL0195, Lipoprotein(a), Elevated Lipoprotein(a), GalNAc-siRNA, Small Interfering RNA
Brief summary
This is a randomized, double-blind, placebo-controlled, single-ascending-dose study to evaluate the safety, tolerability, pharmacokinetics, immunogenicity, and pharmacodynamics of SAL0195 injection in participants with or without elevated lipoprotein(a) \[Lp(a)\]. Approximately 40 male and female participants aged 18 to 65 years will be enrolled across five planned dose cohorts. Participants will receive a single subcutaneous dose of SAL0195 or matching placebo.
Detailed description
This Phase 1 study is designed to evaluate the safety, tolerability, pharmacokinetics, immunogenicity, and pharmacodynamics of a single subcutaneous dose of SAL0195 injection in participants with or without elevated lipoprotein(a) \[Lp(a)\]. The relationship between SAL0195 plasma concentrations and QTc will also be explored, and metabolites in blood and urine will be characterized in selected dose cohorts. The study uses a randomized, double-blind, placebo-controlled, sequential single-ascending-dose design. Five dose levels are planned: 30 mg, 100 mg, 300 mg, 600 mg, and an optional 900 mg dose. Each dose cohort will enroll approximately 8 participants randomized in a 3:1 ratio to SAL0195 or placebo. In the 30 mg cohort, approximately 4 participants without elevated Lp(a) and 4 participants with elevated Lp(a) will be enrolled. Randomization will be stratified by Lp(a) status, with participants within each stratum randomized in a 3:1 ratio to SAL0195 or placebo. The remaining dose cohorts will enroll participants with elevated Lp(a) and will use block randomization in a 3:1 ratio. Each participant will receive only one dose level. Dose escalation will proceed sequentially from the lowest dose after review of available safety, tolerability, pharmacokinetic, and pharmacodynamic data from the preceding cohort. Participants will be followed through Day 85. Participants whose Lp(a) level remains below 60% of baseline at Day 85 will enter an extended follow-up period with visits every 28 days until Lp(a) returns to at least 60% of baseline, the participant reaches approximately 52 weeks after dosing, or the participant withdraws or is lost to follow-up, whichever occurs first.
Interventions
DRUGSAL0195 Injection 30 mg
A single 30 mg dose of SAL0195 injection will be administered subcutaneously on Day 1. SAL0195 injection is supplied at a concentration of 200 mg/mL. The preferred injection site is the abdomen, with the upper arm or thigh as alternative injection sites.
DRUGSAL0195 Injection 100 mg
A single 100 mg dose of SAL0195 injection will be administered subcutaneously on Day 1. SAL0195 injection is supplied at a concentration of 200 mg/mL. The preferred injection site is the abdomen, with the upper arm or thigh as alternative injection sites.
DRUGSAL0195 Injection 300 mg
A single 300 mg dose of SAL0195 injection will be administered subcutaneously on Day 1. SAL0195 injection is supplied at a concentration of 200 mg/mL. The preferred injection site is the abdomen, with the upper arm or thigh as alternative injection sites.
DRUGSAL0195 Injection 600 mg
A single 600 mg dose of SAL0195 injection will be administered subcutaneously on Day 1. SAL0195 injection is supplied at a concentration of 200 mg/mL. The preferred injection site is the abdomen, with the upper arm or thigh as alternative injection sites.
DRUGSAL0195 Injection 900 mg
A single 900 mg dose of SAL0195 injection will be administered subcutaneously on Day 1. SAL0195 injection is supplied at a concentration of 200 mg/mL. The preferred injection site is the abdomen, with the upper arm or thigh as alternative injection sites. This dose cohort is optional and may be initiated based on review of available safety, tolerability, pharmacokinetic, and pharmacodynamic data.
DRUGSAL0195 Matching Placebo
A single dose of matching placebo will be administered subcutaneously on Day 1. The placebo is matched to SAL0195 injection in appearance, odor, packaging, and administration characteristics but contains no active SAL0195. The preferred injection site is the abdomen, with the upper arm or thigh as alternative injection sites.
Sponsors
The Third Xiangya Hospital of Central South University
Shenzhen Salubris Pharmaceuticals Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
OTHER
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* 1\. Participants who have fully understood the study, voluntarily provided written informed consent, and are able to comply with the requirements and restrictions specified in the informed consent form. 2\. Male or female participants aged 18 to 65 years, inclusive. 3\. At screening, male participants must weigh at least 50 kg and female participants must weigh at least 45 kg, with a body mass index (BMI) between 19.0 and 28.0 kg/m², inclusive. 4\. For participants required to have elevated lipoprotein(a) \[Lp(a)\], screening Lp(a) must be ≥75 nmol/L or ≥30 mg/dL. The 30 mg dose cohort may include participants with or without elevated Lp(a), as specified in the protocol. 5\. At screening, physical examination, vital signs, hematology, urinalysis, serum chemistry, coagulation tests, viral serology, and glycated hemoglobin results, except for Lp(a), must be normal or show only minor abnormalities considered not clinically significant by the investigator. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) must not exceed the upper limit of normal. 6\. Twelve-lead electrocardiogram findings must be normal or considered not clinically significant by the investigator, with QTcF \<450 ms. 7\. Participants and their partners must have no plans for pregnancy during the study and for 6 months after administration of the study intervention. Participants must agree to use effective contraception during this period. Hormonal contraceptives are prohibited during the study. Participants must not donate sperm or ova for reproductive or assisted reproductive purposes.
Exclusion criteria
* 1\. Women who are pregnant or breastfeeding; women of childbearing potential with a positive pregnancy test; or women of childbearing potential who have had unprotected sexual intercourse within 14 days before the first dose. 2\. Any disease or medical history considered by the investigator to alter or increase bleeding tendency, including but not limited to acute gastritis, gastrointestinal ulcer, allergic purpura, systemic lupus erythematosus, previous intracranial or intraocular hemorrhage, hemophilia, or von Willebrand disease. 3\. A clinically significant acute drug or food allergic reaction within 2 weeks before screening; an allergic constitution, such as allergy to two or more drugs, foods, or pollens; a history of allergic disease such as asthma, urticaria, or eczematous dermatitis; or known or suspected hypersensitivity or clinically significant reaction to the study intervention, related drugs, placebo, or any excipient. 4\. Positive test result for hepatitis B surface antigen, hepatitis C virus antibody, human immunodeficiency virus antibody, or Treponema pallidum-specific antibody. 5\. Any of the following prior to the first dose: * Administration of a small interfering RNA (siRNA) or antisense oligonucleotide within 18 months; * Use of any metabolic enzyme or transporter inhibitor or inducer within 2 weeks; * Use of any prescription drug, over-the-counter drug, traditional Chinese medicine, herbal product, dietary supplement, vitamin, or health supplement within 2 weeks. 6\. Drug abuse, excessive alcohol consumption, or excessive smoking, including: * A history of drug abuse or a positive urine drug screen at screening; * Average alcohol consumption of more than 14 units per week within 3 months before screening, a positive alcohol breath test at screening, or inability to abstain completely from alcohol-containing food or beverages during the study; * Average smoking of more than 5 cigarettes per day within 3 months before screening, or inability to abstain from tobacco products during the study. 7\. Blood donation, including component donation, or blood loss ≥400 mL within 3 months before screening; blood donation or blood loss ≥200 mL or receipt of a blood transfusion within 1 month before screening; or planned donation of blood or blood components during the study or within 1 month after study completion. 8\. Difficulty with blood collection, inability to tolerate repeated venipuncture, or a clinically significant history of needle or blood phobia as judged by the investigator. 9\. Dysphagia or special dietary requirements that prevent compliance with the standardized diet required by the study. 10\. Receipt of a live vaccine, live attenuated vaccine, or any vaccine containing live viral components within 3 months before screening, or planned receipt of such a vaccine during the study or within 1 month after study completion. 11\. Severe trauma or major surgery requiring general anesthesia within 3 months before screening, or planned surgery during the study or within 3 months after study completion, except procedures performed under local anesthesia. 12\. Participation within 3 months before screening in, or current participation in, any interventional clinical study involving administration of an investigational drug or vaccine, including another clinical study of SAL0195 or another cohort of this study. 13\. Any clinically significant disease, medical history, infectious disease, or other condition that, in the investigator's judgment, could interfere with completion of the study or significantly alter drug absorption, metabolism, or elimination, including clinically significant respiratory, cardiovascular, gastrointestinal, genitourinary, hematologic, endocrine, neurologic, psychiatric, or malignant disease, or relevant gastrointestinal, renal, or gallbladder surgery. 14\. Poor compliance or any other factor that, in the investigator's judgment, makes the participant unsuitable for participation in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence and Severity of Injection-Site Reactions | From pre-dose through 72 hours after dosing. | Injection-site reactions, including local signs and symptoms such as erythema, induration, pain, pruritus, and swelling, will be assessed following subcutaneous administration of SAL0195 or matching placebo. |
| Number of Participants With Clinically Significant Changes in Vital Signs | From baseline through the end of the study, up to Day 365 after dosing. | Vital signs will include respiratory rate, body temperature, pulse rate, and systolic and diastolic blood pressure. Clinically significant abnormalities or worsening from baseline will be summarized by treatment and dose cohort. |
| Incidence and Severity of Treatment-Emergent Adverse Events | From study drug administration through the end of the study, up to Day 365 after dosing. | The number and percentage of participants with treatment-emergent adverse events (TEAEs), treatment-related adverse events, serious adverse events (SAEs), treatment-related serious adverse events, and adverse events leading to study discontinuation will be summarized by treatment and dose cohort. Adverse events will be assessed for severity and relationship to the study intervention. |
| Number of Participants With Clinically Significant Physical Examination Abnormalities | From baseline through the end of the study, up to Day 365 after dosing. | Physical examinations will include assessments of the skin and mucous membranes, superficial lymph nodes, head, neck, chest, abdomen, spine and extremities, nervous system, and other clinically relevant findings. Clinically significant abnormalities or worsening from baseline will be summarized. |
| Number of Participants With Clinically Significant Clinical Laboratory Abnormalities | From baseline through the end of the study, up to Day 365 after dosing. | Clinical laboratory evaluations will include hematology, serum chemistry, urinalysis, and coagulation tests. Clinically significant post-baseline abnormalities or worsening from baseline will be summarized by treatment and dose cohort. |
| Number of Participants With Clinically Significant Twelve-Lead Electrocardiogram Abnormalities | From baseline through the end of the study, up to Day 365 after dosing. | Twelve-lead electrocardiograms will be evaluated for clinically significant abnormalities and changes from baseline. Findings will be summarized by treatment and dose cohort. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Terminal Elimination Half-Life of SAL0195 (t1/2) | Pre-dose through 72 hours after dosing. | Terminal elimination half-life of SAL0195 following a single subcutaneous dose. |
| Terminal Elimination Rate Constant of SAL0195 (λz) | Pre-dose through 72 hours after dosing. | Terminal elimination rate constant of SAL0195 estimated from the terminal phase of the plasma concentration-time profile. |
| Apparent Total Clearance of SAL0195 (CL/F) | Pre-dose through 72 hours after dosing. | Apparent total clearance of SAL0195 following subcutaneous administration. |
| Apparent Volume of Distribution of SAL0195 (Vz/F) | Pre-dose through 72 hours after dosing. | Apparent volume of distribution of SAL0195 during the terminal phase following subcutaneous administration. |
| Maximum Observed Plasma Concentration of SAL0195 (Cmax) | Pre-dose through 72 hours after dosing. | Maximum observed plasma concentration (Cmax) of SAL0195 following a single subcutaneous dose of SAL0195 injection. |
| Time to Maximum Observed Plasma Concentration of SAL0195 (Tmax) | Pre-dose through 72 hours after dosing. | Time to reach the maximum observed plasma concentration of SAL0195. |
| Area Under the Plasma Concentration-Time Curve to the Last Quantifiable Concentration (AUClast) | Pre-dose through 72 hours after dosing. | Area under the plasma concentration-time curve of SAL0195 from time zero to the last quantifiable concentration. |
| Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUCinf) | Pre-dose through 72 hours after dosing. | Area under the plasma concentration-time curve of SAL0195 from time zero extrapolated to infinity. |
| Percentage of AUC Extrapolated to Infinity (AUC_%Extrap) | Pre-dose through 72 hours after dosing. | Percentage of the total AUC extrapolated from the last quantifiable concentration to infinity. |
Outcome results
None listed