Zerlasiran Provides Significant Lp(a) Reductions at 48 Weeks, Phase 2 Data Shows

Use of zerlasiran was associated with a meaningful effect on lipoprotein(a) [Lp(a)] levels in patients at high risk of cardiovascular events, according to new phase 2 topline data announced by Silence Therapeutics.

Announced on June 20, 2024, results of the study indicate use of the short interfering RNA (siRNA) agent was associated with statistically significant reductions in baseline Lp(a) relative to placebo therapy, with a median maximum Lp(a) reduction of approximately 90% or greater observed for both doses during the treatment period.¹

“We are encouraged by the strength of the phase 2 data and emerging competitive profile of zerlasiran, which support an infrequent dosing regimen of at least quarterly with the 300 mg dose,” said Steven Romano, MD, head of Research and Development at Silence Therapeutics.¹ “We look forward to advancing zerlasiran to phase 3 as a potential treatment for this major unmet need in cardiovascular disease.”

The revelations of Lp(a)’s association with increased cardiovascular risk has taken lipidology, and cardiology as a whole, by storm in recent years. A reflection of the growing interest and recognition of Lp(a) as a risk factor, the National Lipid Association released an update in March 2024 to their 2019 guidance on Lp(a) in clinical practice, with the latest iteration now calling for all adults to have their Lp(a) checked at least once in their lifetime.^2,3

Zerlasiran is one of a group of therapies specifically targeting Lp(a) being examined in clinical programs. Other agents garnering attention for their potential in this arena include pelacarsen and olpasiran, with the former expecting to have completed their phase 3 trial in 2025.³

Launched in 2023, the phase 2 ALPACAR-360 trial of zerlasiran, formerly known as SLN360, was designed as a multicenter, randomized, double-blind, placebo-controlled study among patients with Lp(a) greater than 125 nmol/L at baseline and considered at high risk of atherosclerotic cardiovascular disease event. The trial enrolled 180 patients and randomized them to 1 of 3 doses of zerlasiran or placebo therapy.^1,3

Of note, patients could be randomized to zerlasiran at 300 mg subcutaneously every 16 or 24 weeks and 450 mg every 24 weeks.¹

The primary outcome of interest for the trial was the time averaged change in Lp(a) from baseline. In March 2024, Silence Therapeutics announce positive topline data from the 36-week point of the trial.¹

In their June 2024 announcement of 48-week results, Silence Therapeutics disclosed results indicating use was associated with a significant reduction from baseline in Lp(a) compared to placebo to 48 weeks and an approximately 90% or greater in median maximum Lp(a) reduction for both doses during the treatment period. The release also noted safety analysis suggested zerlasiran was well tolerated with no serious safety concerns observed in the trial.¹

According to Silence Therapeutics, full results will be presented at a future scientific meeting or publication following completion of the study, which is designed with a 60-week treatment period.¹

References:

1. ^{Silence Therapeutics. Silence Therapeutics Announces Positive Topline 48-Week Data from Phase 2 Study of Zerlasiran in Patients with Elevated Lipoprotein(a). Silence Therapeutics. June 20, 2024. Accessed June 20, 2024. https://silence-therapeutics.com/investors/press-releases/press-releases-details/2024/Silence-Therapeutics-Announces-Positive-Topline-48-Week-Data-from-Phase-2-Study-of-Zerlasiran-in-Patients-with-Elevated-Lipoproteina/default.aspx.}
2. ^{Koschinsky ML, Bajaj A, Boffa MB, et al. A focused update to the 2019 NLA scientific statement on use of lipoprotein(a) in clinical practice. J Clin Lipidol. Published online March 29, 2024. doi:10.1016/j.jacl.2024.03.001}
3. ^{Campbell P. Zerlasiran further cements lp(a)-lowering potential in phase 2 ALPACAR-360 trial. HCP Live. March 18, 2024. Accessed June 20, 2024. https://www.hcplive.com/view/zerlasiran-further-cements-lp-a--lowering-potential-in-phase-2-alpacar-360-trial.}