Zerlasiran 60-Week Data Reinforce Lp(a) Reductions Observed in ALPACAR-360

Steve Nissen, MD
Credit: Cleveland Clinic

Use of zerlasiran provides safe, durable reductions in lipoprotein(a) [Lp(a)] out to at least 60 weeks, according to new data from the ALPACAR-360 trial.

Presented at the American Heart Association (AHA) Annual Scientific Sessions 2024, the latest data from the trial reinforce the benefits of zerlasiran observed for the 36-week primary endpoint analysis.

“These data provide additional information to select the best dose and dosing interval for future zerlasiran Phase 3 trials,” said principal investigator Steven E. Nissen, MD, chief academic officer of the Heart, Vascular and Thoracic Institute at Cleveland Clinic. “Elevated Lp(a) impacts at least 20% of the global population and is a major cause for morbidity and mortality globally. This is a genetic risk factor that we’ve been unable to treat, and I’m excited about the potential for gene-silencing approaches to help these patients.”

Formerly known as SLN360, zerlasiran has made headlines at numerous points throughout the past year. In March 2024, Silence Therapeutics announced topline results from the ALAPCAR-360 trial. In June 2024, Silence Therapeutics announced 48-week data from the trial. According to their June 2024 announcement, 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.¹

Launched in 2023, the phase 2 ALPACAR-360 trial of zerlasiran 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 randomized 178 patients to 1 of 3 doses of zerlasiran or placebo therapy.^1,2,3,4

The trial’s primary outcome was the time-averaged percent change in Lp(a) concentration from baseline to 36 weeks, with follow-up planned for up to 60 weeks.¹

Relative to placebo, AHA 2024 indicated use of zerlasiran was associated withleast-squares mean time-averaged percent change in Lp(a) concentration of −85.6% (95% CI, −90.9% to −80.3%), −82.8% (95% CI, −88.2% to −77.4%), and −81.3% (95% CI, −86.7% to −76.0%) from baseline to week 36 with the 450 mg every 24 weeks, 300 mg every 16 weeks, and 300 mg every 24 weeks groups, respectively. Further analysis suggested the median percent change in Lp(a) concentration at week 36 was −94.5% (IQR, −97.3% to −84.2%) for the 450 mg every 24 weeks group, −96.4% (IQR, −97.7% to −92.3%) for the 300 mg every 16 weeks group, and −90.0% (IQR, −93.7% to −81.3%) for the 300 mg every 24 weeks group.

In his presentation of 60-week data, Nissen highlighted the observed effects of zerlasiran were consistent throughout the duration of the trial. Safety analysis from the trial indicated there were 20 serious adverse events in 17 patients, but none were related to the study drug. Further analysis of safety data suggested the most common treatment-related adverse effects were injection site reactions, with mild pain occurring in 2.3% to 7.1% of participants in the first day following drug administration.¹

“Additional results from the ALPACAR-360 study continue to support the competitive profile of zerlasiran on key clinical endpoints assessing time-averaged reduction, maximum effect and tolerability,” said Curtis Rambaran, MD, chief medical officer at Silence Therapeutics.² “The Phase 2 data show zerlasiran has the potential to provide long term reductions in Lp(a) with infrequent dosing. We look forward to progressing zerlasiran into Phase 3 as a potentially promising new treatment for patients with high Lp(a).”

References:

1. Nissen SE, Wang Q, Nicholls SJ, et al. Zerlasiran—A Small-Interfering RNA Targeting Lipoprotein(a): A Phase 2 Randomized Clinical Trial. JAMA. Published online November 18, 2024. doi:10.1001/jama.2024.21957
2. Silence Therapeutics. Silence Therapeutics Presents Late-Breaking Phase 2 Zerlasiran Data at 2024 American Heart Association (AHA) Annual Meeting. Silence Therapeutics. November 18, 2024. Accessed November 18, 2024. https://silence-therapeutics.com/investors/press-releases/press-releases-details/2024/Silence-Therapeutics-Presents-Late-Breaking-Phase-2-Zerlasiran-Data-at-2024-American-Heart-Association-AHA-Annual-Meeting/default.aspx.
3. Campbell P. Zerlasiran further cements lp(a)-lowering potential in phase 2 ALPACAR-360 trial. HCP Live. March 18, 2024. Accessed November 18, 2024. https://www.hcplive.com/view/zerlasiran-further-cements-lp-a--lowering-potential-in-phase-2-alpacar-360-trial.
4. Campbell P. Zerlasiran provides significant lp(a) reductions at 48 weeks, phase 2 data shows. HCP Live. June 20, 2024. Accessed November 18, 2024. https://www.hcplive.com/view/zerlasiran-provides-significant-lp-a-reductions-at-48-weeks-phase-2-data-shows.