Safety and Efficacy of an Antisense Oligonucleotide to Apo(a) in Patients with Elevated Lp(a): ISIS-APO(a)Rx Phase 1 Trial

This first-in-human Phase 1 randomized double-blind placebo-controlled trial administered ISIS-APO(a)Rx — an antisense oligonucleotide (ASO) targeting the LPA mRNA to reduce apo(a) synthesis — to 47 patients with elevated Lp(a), in single and multiple ascending doses.

ISIS-APO(a)Rx (subsequently developed as pelacarsen/TQJ230) produced dose-dependent Lp(a) reductions of up to 67–80% from baseline, with an acceptable safety profile at all doses tested. OxPL/ApoB — the principal pro-inflammatory oxidized phospholipid cargo of Lp(a) — was reduced proportionally to Lp(a) reduction. The drug was administered subcutaneously every 1–4 weeks with no clinically significant liver function changes at tested doses.

This Phase 1 study established the pharmacological proof of concept for hepatocyte-targeted ASO therapy as a Lp(a)-lowering mechanism, demonstrating reductions substantially larger than anything achievable with existing therapies (PCSK9 inhibitors reduce Lp(a) by only ~20–25%). The technology — modified RNA targeting the hepatic production of apo(a), the defining protein of Lp(a) — advances to Phase 3 in the HORIZON trial, which will determine whether 80% Lp(a) reduction translates into cardiovascular event reduction.

The clinical significance rating is high because the therapeutic approach — if validated in HORIZON — would transform the management of patients with elevated Lp(a), a high-risk population currently lacking specific effective treatment.

We rate the evidence strong for a Phase 1 study. A rigorously designed first-in-human trial demonstrating that the ASO pelacarsen can reduce Lp(a) by up to 80% safely — the foundational pharmacological study for a therapeutic class that may address the major remaining unmet need in cardiovascular risk management.