Takeaway

A single subcutaneous injection of a short interfering RNA (siRNA), SLN360, was well tolerated and resulted in significant reductions in plasma lipoprotein(a) (Lp[a]) levels in a small phase 1 trial.

Why this matters

Lp(a) is a key risk factor for atherothrombotic cardiovascular disease (CVD) and aortic stenosis, which has largely remained untargeted by drug treatments.

Study design

In the double-blind, ascending dose, phase 1 APOLLO trial, 32 participants with plasma Lp(a) levels of ≥150 nmol/L at baseline and without clinically overt CVD were randomly assigned to receive either placebo (n=8) or single subcutaneous doses of SLN360 at 30 mg (n=6), 100 mg (n=6), 300 mg (n=6), or 600 mg (n=6).
Follow-up visits were conducted at 7, 14, 30, 45, 60, 90 and 150 days following administration.
The primary outcomes were safety and tolerability.
The secondary outcomes included changes in plasma Lp(a) levels over 150 days.
Funding: Silence Therapeutics PLC.

Key results

Treatment-emergent adverse events (AEs) were usually mild, the most common being headache and grade 1 and 2 injection site reactions.
One participant experienced two serious AE episodes, both of which were deemed to be unrelated to the study drug.
The dose-dependent maximal median changes in plasma Lp(a) levels over 150 days were:
- –20 (interquartile range [IQR], –61 to 3) nmol/L in the placebo group;
- –89 (IQR, –119 to –61) nmol/L in the 30 mg group;
- –185 (IQR, –226 to –163) nmol/L in the 100 mg group;
- –268 (IQR, –292 to –189) nmol/L in the 300 mg group; and
- –227 (IQR, –270 to –174) nmol/L in the 600 mg group.
The maximal median percentage changes in plasma Lp(a) over 150 days were:
- –10% (IQR, –16% to 1%) in the placebo group;
- –46% (IQR, –64% to –40%) in the 30 mg group;
- –86% (IQR, –92% to –82%) in the 100 mg group;
- –96% (IQR, –98% to –89%) in the 300 mg group; and
- –98% (IQR, –98% to –97%) in the 600 mg group.

Limitations

Small sample size.
Findings may not be generalizable to a more diverse population.
Patients with atherosclerotic CVD were excluded.

Expert commentary
In response to a question by panelist Vera Bittner, MD, on whether baseline Lp(a) levels could possibly influence the absolute reduction, the lead author, Steven E Nissen, MD, said: “Because these agents so effectively degrade mRNA, I think it is very likely that we're gonna see robust suppression of plasma levels, virtually regardless of the baseline levels.”

ACC 2022 — 'Gene silencing' therapy shows early promise in Lp(a) reduction

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