Table 3 A summary of the most recently completed clinical trials for each gene therapy discussed

Inclisiran (siRNA)¹

ORION-9 [45]

Inclisiran 300 mg or placebo every six months

1. Between-group %∆ in LDL-C

from baseline to day 510

2. Time-adjusted %∆ in baseline LDL-C between day 90 and day 540

18 months

HeFH

482

1. -47.9% between-group difference in LDL-C at day 510 (95% CI, −53.5 to −42.3; P < 0.001)

2. -44.3% between-group difference in LDL-C between day 90 and day 540 (95% CI, −48.5 to −40.1; P < 0.001)

Injection site reactions, gastroenteritis, back pain and nasopharyngitis

ORION-10 [46]

Inclisiran 300 mg or placebo every six months

1. Between-group %∆ in LDL-C

from baseline to day 510

2. Time-adjusted %∆ in baseline LDL-C between day 90 and day 540

18 months

Established ASCVD

1561

1. −52.3% between-group difference in LDL-C at day 510 (95% CI, −55.7 to −48.8; P < 0.001)

2. -53.8% between-group difference in LDL-C between day 90 and day 540 (95% CI,

−56.2 to −51.3; P < 0.001)

Death from cardiovascular causes, fatal or nonfatal stroke, fatal or nonfatal MI, injection site reactions, diabetes mellitus, bronchitis, dyspnea, upper respiratory tract infections

ORION-11 [46]

Inclisiran 300 mg or placebo every six months

1. Between-group %∆ in LDL-C from baseline to day 510

2. Time-adjusted

%∆ in baseline LDL-C between day 90 and day 540

18 months

Established ASCVD and ASCVD risk equivalents

1617

1. -49.9% between-group difference in LDL-C at day 510 (95% CI, −53.1 to −46.6; P < 0.001)

2. -49.2% between-group difference in LDL-C between day 90 and day 540 (95% CI, −51.6 to − 46.8; P < 0.001)

Injection site reaction, arthralgia

Mipomersen (AsO)

Phase 3 (NCT00607373) [34]

200 mg SC QW or placebo

%∆ in LDL-C levels from baseline to week 26

26 weeks

HoFH

51

−24.7% mean LDL-C change in mipomersen group

1. -3.3% mean LDL-C change in placebo group

Injection site reaction

Phase 3

(NCT00794664) [35]

200 mg SC QW or placebo

%∆ in LDL-C from baseline to 2 weeks after last dose

26 weeks

Severe hypercholesterolemia

58

−35.9% mean LDL-C change in mipomersen group

1. + 12.5% mean LDL-C change in placebo group

Injection site reaction

Flu-like symptoms

Pelacarsen (AsO)

Phase 2

(NCT03070782) [16]

20 mg QW or Q2W or Q4W, 40 mg Q4W, 60 mg Q4W or placebo

%∆ in fasting Lp(a) level from baseline to month 6

6–12 months

Established CVD and Lp(a) > 60 mg/dL

286

−72% in 60 mg Q4W group

− 80% in 20 mg QW group

Injection site reaction

Olpasiran (siRNA)

Phase 1 [17]

3, 9, 30, 75, or 225 mg olpasiran once off or placebo

1. Treatment-emergent adverse events

2. Safety laboratory analytes

3. Vital signs

4. ECGs

⁓ 7 months

Lp(a) ≥ 70 nmol/L

64

−80% mean reduction in Lp(a) at Day 113

Headache

Upper respiratory tract infection

Vupanorsen (AsO)

Phase 2

(NCT03371355) [36]

20 mg QW, 40 or 80 mg Q4W

%∆ in fasting triglycerides from baseline to week 24

24 weeks

Hypertriglyceridemia, Type 2 Diabetes Mellitus (T2DM), and Nonalcoholic Fatty Liver Disease

105

− 53% reduction in triglycerides in 80 mg Q4W group

Injection site reaction

ARO-ANG3 (siRNA)

Phase 1

(NCT03747224) [37, 38]

100, 200 or 300 mg ARO-ANG3 or placebo Q4W

• Number of participants with adverse events potentially related to treatment

113 days

Healthy volunteers, FH and severe hypertriglyceridemia

94

−90% reduction in ANGPTL3 in healthy volunteers and patients with FH

− 43% reduction in TG in FH patients

Headache, injection site reaction, upper respiratory tract infection

Volanesorsen (AsO)

APPROACH [39]

Volanesorsen 300 mg QW or placebo

• %∆ in fasting triglyceride level from baseline to 3 months

52 weeks

Familial chylomicronemia syndrome

66

−77% or − 19.3 mmol/L in fasting TG from baseline to month 3 (95% CI, 15.0–23.6 mmol/L, P < 0.001)

Injection site reaction, thrombocytopenia

COMPASS [40]

Volanesorsen 300 mg QW or placebo

• %∆ in fasting triglyceride level from baseline to 3 months

26 weeks

Hypertriglyceridemia

113

− 72.7 ± 17.4% in TG from baseline to month 3

Injection site reaction

BROADEN [41]

Volanesorsen 300 mg QW or placebo

• ∆ in fasting triglycerides from baseline

52 weeks

Familial partial lipodystrophies

40

−88% in fasting TG in volanesorsen group

−22% in fasting TG in placebo group

Injection site reaction, thrombocytopenia

Olezarsen (AsO)

Phase 2 (NCT03385239) [42]

10 or 50 mg Q4W, 15 mg Q2W, 10 mg QW

• %∆ in fasting triglyceride level from baseline to 6 months

12 months

Established ASCVD and hypertriglyceridemia

114

−60% in fasting TG with 10 mg QW and 50 mg Q4W vs 6% increase in placebo group

Injection site reaction

ARO-APOC3 (siRNA)

Phase 1

(NCT03783377) [40, 41, 43]

10, 25 or 50 mg ARO-APOC3 or placebo

• Number of participants with adverse events potentially related to treatment

113 days

Healthy volunteers, hypertriglyceridemia and familial chylomicronemia syndrome

80

− 72% in TG for healthy volunteers

−78% in TG for hypertriglyceridemia and familial chylomicronemia

Injection site reaction, headache, upper respiratory tract infection and two cases of transient elevated ALT