Table 1.
List of siRNAs reported in the text and main clinical trials conducted on them.
| Trial | Subjects and Sample Size (n) | Objectives | Results | Phase | |
|---|---|---|---|---|---|
| ORION-9 | Subjects with HeFH and elevated LDL-C (482) | To evaluate the effect of inclisiran 300 mg compared to placebo in LDL-C lowering | A 39.7% (95% CI, −43.7 to −35.7) LDL-C lowering at day 510 with inclisiran | Phase III | |
| ORION-10 | Subjects with established ASCVD (1561) | To evaluate the effect of inclisiran 284 mg compared to placebo in LDL-C lowering | A 52.3% (95% CI, 48.8 to 55.7) LDL-C lowering with inclisiran | Phase III | |
| Inclisiran | ORION-11 | Subjects with ASCVD equivalent risk (1617) | To assess efficacy and safety of inclisiran 284 mg compared to placebo in LDL-C lowering | A 49.2% (95% CI, 46.6 to 53.1) LDL-C lowering with inclisiran | Phase III |
| HPS-4/TIMI 65/ORION-4 | Subjects with established ASCVD (16124) | To evaluate if inclisiran 300 mg reduces the risk of MACE | Expected in July 2026 | Phase III | |
| VICTORION-2P | Subjects with established ASCVD (16500) | To evaluate if inclisiran 300 mg reduces the risk of MACE | Expected in October 2027 | Phase III | |
| NCT03626662 | Subjects with elevated plasma Lp(a) (80) | To assess safety, tolerability, pharmacokinetics, and pharmacodynamic effects of olpasiran | A safe and persisting 71–97% reduction in Lp(a) concentration | Phase I | |
| Olpasiran | OCEAN(a)-DOSE | Subjects with established ASCVD and a serum Lp(a) concentration of more than 150 nmol/L (~70 mg/dL) (281) | To evaluate the percent change in the Lp(a) concentration from baseline to week 36 with four different doses of olpasiran | Serum Lp(a) levels significantly reduced in a dose-dependent manner at 36 weeks | Phase II |
| OCEAN(a)-Outcomes (NCT05581303) | Subjects with established ASCVD and elevated plasma Lp(a) (6000) | To evaluate if olpasiran reduces the risk of coronary heart disease death, myocardial infarction, or urgent coronary revascularization | Expected in December 2026 | Phase III | |
| Lepodisiran | NCT04914546 | Subjects without CV disease and with a serum Lp(a) concentration of 75 nmol/L or greater (or ≥30 mg/dL) | To assess the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of lepodisiran | A safe and persisting 41–94% reduction in Lp(a) concentration | Phase I |
| ARO-APOC3 | NCT03783377 | Healthy subjects and subjects with hypertriglyceridemia (112) | To assess the safety, tolerability, pharmacokinetics, and pharmacodynamic effects of ARO-APOC3 | ARO-APOC3 associated with few adverse events and reduced serum levels of APOC3 and triglycerides | Phase I |
| NCT01961921 | Subjects with vATTR-polyneuropathy (27) | To assess safety, effects on serum TTR levels, and clinical parameters (mNIS + 7 and multiple disease-relevant measures) of patisiran treatment (0.3 mg/kg intravenously every 3 weeks) | No drug-related adverse events leading to treatment discontinuation, sustained reduction in mean transthyretin levels, a mean 6.95-point improvement in mNIS + 7 from baseline | Phase II | |
| Patisiran | APOLLO | Subjects with vATTR-polyneuropathy (225); cardiac subpopulation with a left ventricular wall thickness ≥ 13 mm without history of hypertension or aortic valve disease (126) | To evaluate the effect of patisiran treatment (0.3 mg/kg intravenously every 3 weeks) on neurological symptoms compared to placebo | Least-squares mean (±SE) change from baseline of mNIS + 7 was −6.0 ± 1.7 versus 28.0 ± 2.6 (difference, −34.0 points; p < 0.001) at 18 months; effects also on gait speed and modified BMI; in the cardiac subpopulation, patisiran reduced mean left ventricular wall thickness (least-squares mean difference ± SEM: –0.9 ± 0.4 mm, p = 0.017), interventricular septal wall thickness, posterior wall thickness, and relative wall thickness; increased end-diastolic volume and reduced NT-proBNP. In a post-hoc analysis, patisiran treatment lowered combined all-cause hospitalization and mortality compared with placebo at month 18 | Phase III |
| APOLLO-B | Subjects with both wild-type and vATTR-cardiomyopathy with clinical evidence of HF and an elevated NT-proBNP between 300 ng/L and 8500 ng/L (360) | To evaluate the efficacy of patisiran treatment (0.3 mg/kg intravenously every 3 weeks) compared to placebo in patients with cardiomyopathy: change from baseline in the distance covered on 6MWT, change from baseline in the KCCQ-OS score, differences in death from any cause, CV events, hospitalizations for any cause, and urgent HF visits over 12 months | The decline in the 6MWT was lower in the patisiran group (95% CI, 0.69 to 28.69; p = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; p = 0.04). Significant benefits were not observed for secondary endpoints (all-cause hospitalization, urgent HF visits, and death) | Phase III | |
| Vutrisiran | HELIOS-A | Subjects with vATTR-polyneuropathy (164) | To evaluate the effect of vutrisiran 25 mg every 3 months on neurological symptoms compared to patisiran and placebo | Change from baseline in mNIS + 7 at 9 months (p = 3.54 × 10−12); significant improvements versus external placebo in Norfolk Quality of Life-Diabetic Neuropathy, 10-m walk test, mNIS + 7 | Phase III |
| HELIOS-B | Subjects with both wild-type and vATTR-cardiomyopathy (655) | To evaluate the efficacy and safety of vutrisiran 25 mg every 3 months compared to placebo in patients with ATTR amyloidosis and cardiomyopathy. Composite endpoint of all-cause mortality and recurrent CV events | Expected in early 2024 | Phase III | |
| NCT03934307 | Patients with arterial hypertension (107) | To assess safety, pharmacokinetics, and pharmacodynamic effects of single doses of zilebesiran (10, 25, 50, 100, 200, 400, or 800 mg), and the change from baseline in systolic and diastolic BP | Single doses of zilebesiran (≥200 mg) associated with decreases in systolic (>10 mmHg) and diastolic BP (>5 mmHg) by week 8 and sustained to week 24. Mild ISRs | Phase I | |
| Zilebesiran | KARDIA-1 | Subjects with a daytime mean systolic BP ≥135 mmHg and ≤160 mmHg (378) | To evaluate the efficacy of different doses of zilebesiran compared to placebo in patients with hypertension | Change in ambulatory systolic BP: –11.1 mmHg for zilebesiran 150 mg every 6 months vs. –14.5 mmHg for zilebesiran 300 mg every 6 months vs. –4.1 mmHg for zilebesiran 300 mg every 3 months vs. –14.2 mmHg for zilebesiran 600 mg every 6 months (p < 0.05 for each group) | Phase II |
| KARDIA-2 | Subjects with hypertension not adequately controlled by a standard of care antihypertensive medication (672) | To evaluate the efficacy of zilebesiran compared to placebo in patients with hypertension | Expected in early 2024 | Phase II |
HeFH: heterozygous familial hypercholesterolemia; LDL-C: low-density lipoprotein cholesterol; ASCVD: atherosclerotic cardiovascular disease; MACE: major adverse cardiovascular events; Lp(a): lipoprotein(a); APOC3: apolipoprotein C-III; HF: heart failure; vATTR: variant transthyretin amyloidosis; mNIS: modified Neuropathy Impairment Score; 6MWT: 6 min walking test; KCCQ: Kansas City Cardiomyopathy Questionnaire; BP: blood pressure; ISR: injection site reaction.