. 2021 Mar 26;118(5):1218–1231. doi: 10.1093/cvr/cvab100

Table 2.

Lp(a)-lowering RNAi therapeutics in development

Drug	RNAi technology	Industrial sponsor	Stage of development	Route of delivery	Efficacy data to-date	Safety data to-date
AKCEA-APO(a)-L_Rx	ASO	Novartis—Ionis/Akcea	Phase 3	Sub-cutaneous injection	Dose-dependent Lp(a) lowering in Phase 2 clinical trial in adults with Lp(a) ≥60 mg/dL (≈≥150 nmol/L) and established CVD. Up to 80% reduction (75.1 mg/dL; 187.8 nmol/L) at highest (20 mg weekly) dose in patients with median baseline Lp(a) 224.3 nmol/L (IQR 177.2–286.9).¹⁰⁷	Adverse events (AEs) more frequent in active arms (90%) than in placebo arm (83%); serious AEs followed a similar pattern (10% active arms; 2% placebo arm). Injection site reactions were the most common AE.¹⁰⁷
ARC-LPA/AMG890	GalNAc–siRNA	Amgen-Arrowhead	Phase 2	Sub-cutaneous injection	Phase 1 clinical trial showed Lp(a) reduction of over 90% at doses ≥9 mg/kg that persisted 3–6 months.¹²⁶ (https://clinicaltrials.gov/ct2/show/NCT03626662). Phase 2 clinical trial under way (https://clinicaltrials.gov/ct2/show/NCT04270760). In cynomolgus monkeys, 85–90% Lp(a) reduction at 29 days after 3 doses at 3 mg/kg Q1W; >75% reduction persisted at 6 weeks after third dose.¹³⁹	In phase 1 study data, there was no excess of adverse events with AMG890.¹²⁶
SLN360	GalNAc–siRNA	Silence Therapeutics	Phase 1	Sub-cutaneous injection	Phase 1 clinical trial starting in 2021 (https://clinicaltrials.gov/ct2/show/NCT04606602). In cynomolgus monkeys, >95% Lp(a) reduction at 29 days after 3 doses at 3 mg/kg Q1W; >95% reduction persisted at 7 weeks after third dose.¹⁴⁰	Non-clinical safety studies in Cynomolgus monkey showed no observed adverse effect level was >60-fold greater than pharmacological active dose; <1% of peak liver exposure in tissues outside liver and kidney.¹⁴¹

Drug

RNAi technology

Industrial sponsor

Stage of development

Route of delivery

Efficacy data to-date

Safety data to-date

AKCEA-APO(a)-L_Rx

ASO

Novartis—Ionis/Akcea

Phase 3

Sub-cutaneous injection

Dose-dependent Lp(a) lowering in Phase 2 clinical trial in adults with Lp(a) ≥60 mg/dL (≈≥150 nmol/L) and established CVD. Up to 80% reduction (75.1 mg/dL; 187.8 nmol/L) at highest (20 mg weekly) dose in patients with median baseline Lp(a) 224.3 nmol/L (IQR 177.2–286.9).¹⁰⁷

Adverse events (AEs) more frequent in active arms (90%) than in placebo arm (83%); serious AEs followed a similar pattern (10% active arms; 2% placebo arm). Injection site reactions were the most common AE.¹⁰⁷

ARC-LPA/AMG890

GalNAc–siRNA

Amgen-Arrowhead

Phase 2

Sub-cutaneous injection

Phase 1 clinical trial showed Lp(a) reduction of over 90% at doses ≥9 mg/kg that persisted 3–6 months.¹²⁶ (https://clinicaltrials.gov/ct2/show/NCT03626662).

Phase 2 clinical trial under way (https://clinicaltrials.gov/ct2/show/NCT04270760).

In cynomolgus monkeys, 85–90% Lp(a) reduction at 29 days after 3 doses at 3 mg/kg Q1W; >75% reduction persisted at 6 weeks after third dose.¹³⁹

In phase 1 study data, there was no excess of adverse events with AMG890.¹²⁶

SLN360

GalNAc–siRNA

Silence Therapeutics

Phase 1

Sub-cutaneous injection

Phase 1 clinical trial starting in 2021 (https://clinicaltrials.gov/ct2/show/NCT04606602).

In cynomolgus monkeys, >95% Lp(a) reduction at 29 days after 3 doses at 3 mg/kg Q1W; >95% reduction persisted at 7 weeks after third dose.¹⁴⁰

Non-clinical safety studies in Cynomolgus monkey showed no observed adverse effect level was >60-fold greater than pharmacological active dose; <1% of peak liver exposure in tissues outside liver and kidney.¹⁴¹