Zerlasiran Achieves Significant Sustained Reduction in Lipoprotein(a) Levels with Infrequent Dosing

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Zerlasiran (Silence Therapeutics), a novel N-acetylgalactosamine–conjugated short interfering RNA (siRNA), was found to produce sustained reductions in time-averaged lipoprotein(a) levels of more than 80% with infrequent dosing in the Phase II ALPACAR-360 trial (NCT05537571).^1,2 The study, presented at the American Heart Association’s Scientific Sessions 2024 and published online in the Journal of the American Medical Association, was the first to report time-averaged lipoprotein(a) analyses, which provides a more accurate evaluation of the long-term effects of treatment, including intervals between doses, according to the authors.

“These data provide additional information to select the best dose and dosing interval for future zerlasiran Phase III trials,” study lead author Steven E. Nissen, MD, chief academic officer of the Heart, Vascular and Thoracic Institute at Cleveland Clinic, said in a press release. “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.”³

The study authors noted that recognition is growing around lipoprotein(a) as a likely causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis. They added that concentrations of lipoprotein(a) have not been lowered by traditional preventative measures against ASCVD, such as diet, exercise, and statin medications; however, PCSK9 inhibitors have been found to moderately lower levels.

“Because lipoprotein(a) levels are principally genetically determined, most current strategies for reducing circulating concentrations consist of nucleic acid–based therapies, either an antisense oligonucleotide or a (siRNA) designed to degrade hepatic mRNA responsible for the production of apolipoprotein(a), thereby preventing assembly of lipoprotein(a) particles,” the study authors wrote. “A drug that blocks the binding of apolipoprotein(a) to apolipoprotein B100 is also under development. Determining the optimal dosing strategy for siRNA therapies is challenging because these agents have a long duration of effect, typically ranging from weeks to months. Achieving steady-state reductions in lipoprotein(a) requires a longer time than therapies with shorter pharmacodynamic effects.”¹

The 60-week, multicenter, randomized, double-blind, placebo-controlled ALPACAR-360 trial compared the efficacy, safety, and tolerability of zerlasiran administered subcutaneously vs. placebo in adult patients aged 18-80 years with elevated lipoprotein(a) who have a high risk of ASCVD events.²

Investigators enrolled 180 patients in five groups in a 1:1:2:2:2 ratio, administering placebo every 16 weeks for three doses, placebo every 24 weeks for two doses, zerlasiran 450 mg every 24 weeks for two doses, zerlasiran 300 mg every 16 weeks for three doses, or zerlasiran 300 mg every 24 weeks for two doses. The trial’s primary efficacy outcome was time-averaged percent change in serum lipoprotein(a) concentration for each zerlasiran treatment cohort vs. placebo from baseline through 36 weeks after administration. Secondary endpoints included time-averaged percent changes from baseline to weeks 48 and 60.

The results showed that compared with the pooled placebo cohort, least-squares mean time-averaged percent change in lipoprotein(a) concentration from baseline to week 36 was −85.6% (95% CI, −90.9% to −80.3%) for the 450 mg every 24 weeks cohort, −82.8% (95% CI, −88.2% to −77.4%) for the 300 mg every 16 weeks cohort, and −81.3% (95% CI, −86.7% to −76.0%) for the 300 mg every 24 weeks cohort.

Median (percent change in lipoprotein(a) concentration at week 36 was −94.5% (−97.3% to −84.2%) for the 450 mg every 24 weeks cohort, −96.4% (−97.7% to −92.3%) for the 300 mg every 16 weeks cohort, and −90.0% (−93.7% to −81.3%) for the 300 mg every 24 weeks cohort.

In terms of safety, zerlasiran was well-tolerated, with the most common treatment-related adverse effects (AEs) being injection site reactions. Twenty serious AEs were reported in 17 patients, none of which were considered to be related to zerlasiran, according to the investigators.

“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,” Curtis Rambaran, MD, chief medical officer, Silence Therapeutics, said in a press release. “The Phase II 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 III as a potentially promising new treatment for patients with high Lp(a).”³

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. Evaluate SLN360 in Participants With Elevated Lipoprotein(a) at High Risk of Atherosclerotic Cardiovascular Disease Events. ClinicalTrials.gov. Updated July 31, 2024. Accessed November 20, 2024. https://clinicaltrials.gov/study/NCT05537571

3. Silence Therapeutics Presents Late-Breaking Phase 2 Zerlasiran Data at 2024 American Heart Association (AHA) Annual Meeting. News release. Silence Therapeutics. November 18, 2024. Accessed November 20, 2024. https://www.businesswire.com/news/home/20241118316596/en/Silence-Therapeutics-Presents-Late-Breaking-Phase-2-Zerlasiran-Data-at-2024-American-Heart-Association-AHA-Annual-Meeting