Table 3.

siRNA.

No	Study registration number (ref)	Study Population	Age Group	Intervention Arm	n	Comparator arm	n	Time to follow Up	Primary Endpoint	Outcome: Mean Difference (Treatment vs Placebo)	Adverse Events
INCLISIRAN
1	NCT01437059 (Fitzgerald et al., 2014)	Healthy adults with LDL-C higher than 3.00 mmol/L	18–65 years old	ALN-PCS one dose IV 0.015 mg/kg 0.045 mg/kg 0.090 mg/kg 0.150 mg/kg 0.250 mg/kg 0.400 mg/kg	Total 24 3 3 3 3 6 6	Placebo (NS)	8	Data for adverse event: 28 days Other data: 180 days	Safety, tolerability, and adverse event	Mean percentage change vs placebo: PCSK9 (−45.3, −86.0, −71.5, −96.2, −98.3, −114.5); LDL-C (−6.6, −13.4, −27.2, −24.0, −30.1, −47,2)	Treatment-emergent adverse events (TEAE) (rash, headache, hiccups, cold symptoms, paraesthesia, polyuria or disuria, infusion-site hematoma) ALN-PCS n = 19 (79%) Placebo n = 7 (88%)
2	NCT02314442 (Fitzgerald et al., 2016)	Healthy volunteers with LDL cholesterol level ≥ 100 mg/dl, TG level ≤ 400 mg/dl	18–65 years old sd phase, 18–75 years old md phase	Single dose phase: sc inclisiran (n = 4 each) 25 mg 100 mg 300 mg 500 mg 800 mg (two cohorts for the 800-mg dose). Multi-dose phase: (n = 4-8 each) 125mg/w for 4 weeks, 250mg/2 weeks for 4 weeks, 300 mg/month for 2 months with and without statin, 500 mg/month for 2 months with and without statin	SD 4 each MD 4-8 each	Placebo	SD n = 6, MD phase n = 11 (8 in md phase without statin group and 3 in md phase with statin group)	56 days for sd phase, ≤84 days for md phase. PD end point were evaluated for an additional month (until 180 days after last dose of therapy) after completion of safety and side effect profile assessment	Safety, side effect profile	sd phase: PCSK9 (−46.0; −31.4; −73.9; −69.3; −72.5) sd phase: PCSK9 (<0.05; n/a; <0.001; <0.001; 0.001)	No SAE, most common adverse events were cough, musculoskeletal pain, nasopharyngitis, headache, back pain, and diarrhea. in sd phase (≥5% participant in inclisiran group): 2 of 18 cough, musculoskeletal pain, nasopharyngitis. In md phase (≥10% participant in inclisiran group) 6 of 33 headache, 5 (15%) diarrhea, 5 (15%) back pain, 4 (12%) nasopharyngitis
3	NCT02597127 (Ray et al., 2017)	LDL >70 mg/dL for patient with history ASCVD/>100 mg/dL without history ASCVD max statin therapy	62–74 years old	SD: - Placebo - 200 mg - 300 mg - 500 mg DD: - Placebo - 100 mg - 200 mg - 300 mg	370	Placebo	127	Primary 180 days Other data 210–240 days	Percentage change from baseline in LDL-Cholesterol level	Serious Adverse events Intervention group SD 200 mg 6 (10%); 300 mg 5 (8%); 500 mg 6 (9%); DD 100 mg 11 (18%); 6 (10%); 7 (11%) Placebo SD placebo 3 (5%); DD placebo 6 (10%)
4	NCT03397121 (Raal et al., 2020)	Diagnosed with heterozygous familial hypercholesterolemia LDL at least 100 mg/dL despite max statin therapy	47–64 years old	Inclisiran SC 300 mg Day 1, 90, 270, 450	242	Placebo	240	Day 30, 150, 330, 510, 540	I = Percentage change from baseline LDL - C levels on day 510 II = time-averaged percent change in the LDL - C level between day 90 and day 540	I = −47.9% (95% CI, −53.5 to −42.3; P < 0.001) II = −44.3% (95% CI, −48.5 to −40.1; P < 0.001)	Patients with ≥ 1 serious adverse event - Intervention group 18 (7.5%), 1 death from cardiovascular cause 1 (0.4%) - Control 33 (13.8%)
5	NCT03400800 (Ray et al., 2020)	high risk, primary prevention patients or those with ASCVD (secondary prevention)	≥18 years old	Inclisiran 300 mg SD SC Day 1, 90, 270, 450	98	Placebo	105	up to day 540	Percentage change in LDL-C from baseline at day 510 and time adjusted percentage change in LDL-C from baseline after day 90 and up to day 540	LDL-C changes from baseline to day 510 (−43.7%). Time adjusted change in LDL-C from baseline after day 90 up to day 540 (−41.0%). Absolute change difference of LDL-C is -.5 mmol/dL (−58.4 mg/dL) between groups P < 0.0001, <0.0001, <0.0001	SAE, AE at injection site Intervention: SAE (n = 20), AE at injection site (n = 4) Control: SAE (n = 13), AE at injection site (n = 0)
6	Ray et al. (2022)	ITT Population (For efficacy analyses: Pooled analysis of ORION-9,-10 and −11, included patients with heterozygous familial hypercholesterolaemia, atherosclerotic CV disease (ASCVD), or ASCVD risk equivalent on maximally tolerated statin-therapy Population (for Safety analyses) : All patients who received at least 1 dose of Inclisiran/placebo	54–73 years old	Inclisiran 284 mg SD SC Day 1, 90 and 6-monthly until 18months	1833	Placebo	1827	540	Change in LDL- C Levels & Safety population (risk of cardiovascular events)	Change in LDL-C levels day 90: - 50.6% [95% CI (−52.3 to −49.0); P < 0.0001] day 540: - 51.4% [95% CI (−53.4 to −49.4); P < 0.0001] Inclisiran significantly reduced MACE (OR[95%CI]: 0.74 [0.58–0.94]), but not fatal and non-fatal MI (OR [95% CI]: 0.80 [0.50−1.27]) and fatal and non-fatal stroke (OR [95% CI]: 0.86 [0.41−1.81]).	- MACE Intervention: 131 Control:171 - Fatal and non-fatal MI Intervention: 33 Control:41 - Fatal and non-fatal stroke Intervention: 13 Control:15
7	NCT03399370 and NCT03400800 (Ray et al., 2020)	ASCVD, LDL >70, statin and lipid lowering therapy use, GFR >30	adult >18 years old	Inclisiran 284 mg/SC	ORION 10 : 781 ORION 11 : 810	Placebo	780 807	day 30 day 150 day 330 day 510 day 540	Percentage change in LDL time adjusted LDL change (throughout the follow-up period)	−52.3 P < 0.001 −49.9 P < 0.001	Total AEs: 1156 Serious AEs: ORION 10: 175 ORION 11: 181
8	NCT02597127 and NCT03159416 (Wright et al., 2020)	Participant with normal renal function and mild, moderate and severe RI from phase 1 ORION -7 renal study and the phase 2 ORION-1 study; BMI 18–40kg/m2 and BW > 50 kg	18 < age <80 years old	(ORION 7) = SD Placebo and 300 mg; DD Placebo and 300 mg (ORION 1)1 = Normal Function, 2 = Mild RI, 3 = Moderate RI, 4 = Severe RI	ORION 1 = 122 ORION 7 = 31	Placebo	ORION 1 = 125 ORION 7 = 0	180 days atau max 360 days	ORION 7: PK, Safety, PD ORION 1: PK, Safety	Participants with at least 1 TEAE (treatment-emergent adverse event) Intervention: 126 Control: 101
9	Raal et al. PMID: 36217872	HeFH ASCVD ASCVD-risk equivalent	adults	Inclisiran 284 mg/SC	148	Placebo	150	510 days	LDL percentage change at day 510 time-averaged percentage LDL change	−54.2% P < 0.0001	Participants with ≥1 TEAEs: 233 Serious TEAEs: Intervention: 32 Placebo: 37
PATISIRAN
1	NCT01148953 and NCT01559077 (Coelho et al., 2013)	ALLN 01:biopsy-confirmed TTR amyloidosis mild-moderate neuropathy karnofsky performance status >60 BMI 18.5–33 NYHA II or less adequate liver, renal, thyroid function not pregnant/childbearing potential ALLN 2: 18-45, healthy, BMI 18–31.5.	adults >18 years old	ALN-TTR01 (0.01–1.0 mg/kg) - IV ALN-TTR02 (0.01–0.5 mg/kg) - IV	24 13	Placebo	8 4	70 days	reduction in TTR level	−38% (dosage 1.0 mg/kg) P 0.01 ALLN 02 0.15 = −85.7% P 0.001 0.3 = −87.6% P 0.001 0.5:= −93.8% P 0.001	ALN-TTR01 Infusion Reaction: 5 Fatigue: 2 Placebo: 0 ALN-TTR02 Skin Erythema: 6 Infusion Reaction: 1 Placebo: 2 (Skin Erythema)
2	NCT01961921 (Coelho 2020)	hATTR amyloidosis	29–77 years old	Patisiran 0.3 mg/kgbb - IV once/3 weeks	Patisiran alone (n = 7)	Patisiran + TTR tetramer stabilizer	n = 19	24 months	The primary objective was to evaluate the safety and tolerability of long-term dosing with patisiran.	(-0.28)	SAE 7, death 2, any AE leading to discontinuation 2. None of which were considered related to Patisiran flushing (n = 7), infusion-related reactions (n = 6), diarrhea (n = 3)
3	NCT01960348 (Solomon et al., 2019)	Patients with hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy and cardiac amyloidosis	61 (54-67) years old	Patisiran 0.3 mg/kgbb - IV once/3 weeks	90 (71.4%) patisiran	Placebo	36 (28.6%) placebo	18 months	improved left ventricular (LV) global longitudinal strain (LV GLS)	Patisiran improved the absolute GLS (least-squares mean [SE] difference, 1.4% [0.6%]; 95% CI, 0.3%-2.5%; P = 0.02) compared with placebo at 18 months, with the greatest differential increase observed in the basal region (overall least-squares mean [SE] difference, 2.1% [0.8%]; 95% CI, 0.6%-3.6%; P = 0.006) and no significant differences in the mid and apical regions among groups
4	NCT01960348	Had a diagnosis of hATTR amyloidosis with a documented TTR mutatiom and symptomatic neuropathy, were ambulatory, had adequate liver function and adequate renal function, and were included in the prespecified cardiac subpopulation (baseline LV wall thickness >13 mm, no history of aortic valve disease or hypertension) Enrolled participants which did not fulfill criteria to be included in prespecified cardiac subpopulation	18–85 years old	Patisiran 0.3 mg/kgbb - IV once/3 weeks	Cardiac subpopulation 90	Placebo	36	Echo parameters at 18 months NTproBNP and 10MWT gait speed at 9 months and 18 months	Reduction of left ventricular wall thickness, interventricular septal wall thickness, posterior wall thickness, and relative wall thickness. Increase of end diastolic volume, decrease of global longitudinal strain, increase of cardiac output. Decrease of NT pro BNP. Increase of 10MWT gait speed. No significant outcome in echo parameters. Decrease of NTproBNP. Increase of 10MWT gait speed.	Reduction in mean LV wall thickness (least-squares mean difference±SEM, −0.9 ± 0.4 mm; P = 0.017) was observed with patisiran compared with placebo. In patisirantreated patients compared with placebo, global longitudinal strain was decreased (−1.4% ± 0.6%, P = 0.015), cardiac output was increased (0.38 ± 0.19 L/min, P = 0.044), and LVEDV was increased (8.31 ± 3.91 mL, P = 0.036) Patisiran reduced NT-proBNP compared with placebo at 9 months (ratio of fold change patisiran/placebo, 0.63; 95% CI, 0.50–0.80) and 18 months (ratio of fold change patisiran/placebo, 0.45; 95% CI, 0.34– 0.59; P = 7.7 × 10–8), corresponding to a 55% reduction relative to placebo	Cardiac serious adverse events Intervention: 20 Control: 10
5	NCT01960348	hereditary transthyretin amyloidosis with polyneuropathy, some patients has cardiac abn (NYHA I dan II)	18–85 years old	Patisiran 0.3 mg/kgbb - IV once/3 weeks	148	Placebo	77	18 months	mNIS+7, LVthickness, LVLStrain	−34; −0.9; −1.37 <0.001; 0.02; 0.02	diarreha, edema, nausea, cough, asthenia, death, etc Intervention: 143 Control: 75
6	NCT01960348	Hereditary transthyretin amyloidosis with polyneuropathy, some patients has cardiac abn (NYHA I dan II)	n/a	Patisiran 0.3 mg/kgbb - IV once/3 weeks	148 (90 yg cardiac)	Placebo	77 (36 yang cardiac)	18 months	measures of overall QoL	AEs not reported
REVUSIRAN
1	NCT02319005 (Judge et al., 2020)	TTR mutation and amyloid deposits, hx of hf and cardiac involvement on echo	18–90 years old	Revusiran 500mg/SC	140	Placebo	66	18 months	6MWT, Troponin I, NTpBNP	the study was prematurely discontinued due to an imbalance of deaths observed in the revusiran group (18 patients, 12.9%) compared with the placebo group (2 patients, 3.0%) during the on-treatment period
SLN360
1	NCT04606602 or 2020-002471-35 (Nissen et al., 2022)	no known CVDs Lp(a) conc >150 nmol/L BMI 18–45 kg/m2	adults 36–63 years old	SLN360 SD 30 mg/SC 100 mg/SC 300 mg/SC 600 mg/SC	24 (6 each dose)	Placebo	8	150 days	Safety and tolerability	Participants with any treatment-emergent adverse event intervention group: 100% placebo group: 75%