Hyperlipidemia
Conditions
Brief summary
This is a Phase II multi-center, open-label extension (OLE) clinical trial of HRS-7249, a GalNAc-conjugated APOC3-targeted siRNA injection, enrolling two cohorts of participants. Cohort 1 includes subjects who completed parent study HRS-7249-201 within 24 weeks; Cohort 2 newly recruited patients with fasting triglyceride (TG) ≥2.3 mmol/L aged 18-79 years. All participants receive subcutaneous HRS-7249 for a 48-week treatment period followed by a 24-week safety follow-up phase, with two dosing regimens. The primary objective is to assess long-term safety and tolerability of repeated HRS-7249 administration. Secondary objectives include evaluating sustained lipid-lowering effects on TG, APOC3 and other lipid profiles, impacts on glycometabolism, incidence of acute pancreatitis and major adverse cardiovascular events (MACE), long-term pharmacokinetic/pharmacodynamic (PK/PD) profiles, and anti-drug antibody (ADA) dynamics. All safety assessments including vital signs, physical examinations, laboratory tests, 12-lead ECG, injection site reactions and adverse events will be collected throughout the study. Lipid parameters, HbA1c, pancreatitis and cardiovascular events will be monitored to characterize the clinical benefit-risk profile of long-term HRS-7249 therapy in hypertriglyceridemia patients. A total of at least 400 subjects will be enrolled nationwide in China.
Interventions
Dosing level: Low dose
Sponsors
Fujian Shengdi Pharmaceutical Co., Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
No
Inclusion criteria
\- Cohort 1 (Roll-over participants from HRS-7249-201) 1. Able to understand trial procedures, voluntarily participate and provide written informed consent; 2. Completed last visit of parent study HRS-7249-201 within 24 weeks prior to screening; 3. Male or female subjects aged ≥18 and \<80 years at consent signature. Cohort 2 (Newly enrolled participants) 1\. Able to understand trial procedures, voluntarily participate and provide written informed consent; 2. Fasting triglyceride ≥2.3 mmol/L at screening; 3. Male or female subjects aged ≥18 and \<80 years at consent signature.
Exclusion criteria
\- Cohort 1 Exclusion 1. Permanently discontinued parent study treatment due to treatment-related adverse events (TRAE); 2. Persistent clinically significant adverse events or lab abnormalities unresolved by parent study final visit, judged by investigator to increase risk of continued dosing; 3. Unstable or severe hepatic, renal, cardiovascular, neurological, endocrine, hematologic disorders that render participation unacceptable; 4. Plan to receive major surgery during study period; 5. Planned plasmapheresis during trial; 6. Intend to use weight-loss drugs or undergo weight-altering surgery during trial; 7. Refuse lifestyle intervention or limit daily alcohol intake below 30 g/day; 8. Pregnant or breastfeeding females; 9. Fertile women without contraception within 30 days pre-screening; fertile male/female subjects refusing contraception and gamete donation restrictions through follow-up; 10. Any other conditions judged unsuitable by investigator. Cohort 2 Exclusion 1\. History of acute pancreatitis within 3 months pre-randomization; 2. Plasmapheresis received or planned within 4 weeks pre-randomization; 3. Malignancy diagnosed within past 5 years (except cured non-melanoma skin cancer/cervical carcinoma in situ); 4. NYHA Class III/IV heart failure at screening/randomization; 5. Acute coronary syndrome, stroke, TIA, major cardiovascular revascularization within past 3 months; 6. Severe symptomatic arrhythmia within 3 months pre-randomization; 7. Severe trauma/major surgery within 6 months or planned major operation during trial; 8. Severe infection within past 3 months; 9. Nephrotic syndrome, severe liver disease, Cushing syndrome interfering with lipid metabolism; 10. Unstable severe multi-organ systemic diseases; 11. Uncontrolled hypertension (SBP≥160 mmHg or DBP≥100 mmHg); 12. Plan to take weight-loss agents or bariatric surgery within 2 months pre-screening; 13. Type 1 DM, newly diagnosed DM within 12 weeks, or HbA1c ≥8.5%; 14. Current/history hyper/hypothyroidism; 15. History of substance/alcohol abuse (daily ethanol \>80 g); 16. Major lifestyle modification within past 4 weeks or refusal of alcohol/lifestyle limits; 17. eGFR \<60 mL/min/1.73m² by MDRD formula; 18. ALT/AST ≥2×ULN; 19. Total/direct bilirubin ≥1.5×ULN; 20. CK \>1.5×ULN; 21. Platelet count \<100×10⁹/L or thrombocytopenia history; 22. Positive HIV/HCV-Ab, or HBsAg positive with HBV-DNA ≥1000 copies/mL; 23. Participated in other interventional drug trials within 3 months pre-screening; 24. Pregnant or lactating women; 25. Fertile subjects without compliant contraception; 26. Any other conditions deemed inappropriate by investigator.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Injection site reactions | 48 weeks |
| All adverse events (AEs) | 72 weeks |
| Respiratory rate | 72 weeks |
| Pulse rate | 72 weeks |
| Systolic and diastolic blood pressure | 72 weeks |
| Body temperature | 72 weeks |
| Complete Blood Count | 72 weeks |
| Blood chemistry | 72 weeks |
| High-sensitivity C-reactive protein (hs-CRP) | 72 weeks； |
| Heart rate | 72 weeks； |
| PR interval | 72 weeks |
| QRS duration | 72 weeks |
| QT interval | 72 weeks |
| QTc interval | 72 weeks |
| Urinalysis | 72 weeks |
Secondary
| Measure | Time frame |
|---|---|
| Percentage change and absolute value change from baseline in ApoB | 72 weeks |
| Percentage change and absolute value change from baseline in ApoA1 | 72 weeks |
| Percentage change and absolute value change from baseline in Lp(a) | 72 weeks |
| Percentage change and absolute value change from baseline in VLDL-C | 72 weeks |
| Percentage change and absolute value change from baseline in HbA1c | 72 weeks |
| Percentage change and absolute value change from baseline in RC | 72 weeks |
| Incidence rate of acute pancreatitis | 72 weeks |
| Incidence rate of major adverse cardiovascular events (MACE, including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina, or coronary revascularization) | 72 weeks |
| Plasma Concentration of long-term HRS-7249 treatment | 72 weeks |
| Dynamics of anti-drug antibody (ADA) following long-term HRS-7249 treatment | 72 weeks |
| Proportion of patients with TG<1.7 mmol/L | 48 weeks |
| Proportion of patients with TG<2.3 mmol/L | 48 weeks |
| Proportion of patients with baseline TG≥5.7 mmol/L achieving TG<5.7 mmol/L | 48 weeks |
| Percentage change and absolute value change from baseline in TG | 72 weeks |
| Percentage change and absolute value change from baseline in APOC3 | 72 weeks |
| Percentage change and absolute value change from baseline in HDL-C | 72 weeks |
| Percentage change and absolute value change from baseline in TC | 72 weeks |
| Percentage change and absolute value change from baseline in LDL-C | 72 weeks |
| Percentage change and absolute value change from baseline in sdLDL-C | 72 weeks |
| Percentage change and absolute value change from baseline in non-HDL-C | 72 weeks |
Countries
China
Contacts
CONTACTChanjuan Deng, MM
CONTACTJianpeng Su, MS
Outcome results
None listed