Zerlasiran, a novel N-acetylgalactosamine–conjugated short interfering RNA (siRNA) developed by Silence Therapeutics, has demonstrated significant and sustained reductions in lipoprotein(a) (Lp(a)) levels in a Phase 2 clinical trial. The ALPACAR-360 trial (NCT05537571) revealed that zerlasiran achieved over 80% reduction in time-averaged Lp(a) levels with infrequent dosing, marking a potential breakthrough in treating elevated Lp(a), a genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic stenosis.
The study, presented at the American Heart Association’s Scientific Sessions 2024 and published in the Journal of the American Medical Association, enrolled 180 patients aged 18-80 years with elevated Lp(a) and a high risk of ASCVD events. Participants were randomized into five groups receiving either placebo or zerlasiran at different doses (300 mg or 450 mg) and dosing intervals (every 16 or 24 weeks) administered subcutaneously over a 60-week period. The primary efficacy outcome was the time-averaged percent change in serum Lp(a) concentration from baseline through 36 weeks.
The results indicated that zerlasiran led to significant reductions in Lp(a) levels compared to the placebo group. Specifically, the least-squares mean time-averaged percent change in Lp(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.
Impact on Cardiovascular Risk
Elevated Lp(a) impacts at least 20% of the global population and is recognized as a significant, genetically determined risk factor for ASCVD. Traditional preventative measures such as diet, exercise, and statins have limited impact on Lp(a) concentrations. While PCSK9 inhibitors have shown moderate reductions, zerlasiran offers a more targeted approach by silencing the LPA gene, which signals the body to produce Lp(a).
Safety and Tolerability
Zerlasiran was generally well-tolerated in the ALPACAR-360 trial. The most common treatment-related adverse effects (AEs) were injection site reactions, with mild pain occurring in 2.3% to 7.1% of participants on the first day after receiving zerlasiran. Twenty serious AEs were reported in 17 patients, but none were considered related to zerlasiran.
Future Directions
Curtis Rambaran, MD, chief medical officer at Silence Therapeutics, stated that the Phase 2 data support zerlasiran's potential to provide long-term Lp(a) reductions with infrequent dosing. The company plans to advance zerlasiran into Phase 3 trials to further evaluate its efficacy and safety as a treatment for patients with high Lp(a). Steven E. Nissen, MD, chief academic officer of the Heart, Vascular and Thoracic Institute at Cleveland Clinic, expressed excitement about the potential for gene-silencing approaches to help patients with this previously untreatable genetic risk factor.
