Zerlasiran, a short interfering RNA (siRNA) developed by Silence Therapeutics, has shown promising results in reducing lipoprotein(a) [Lp(a)] levels in patients with atherosclerotic cardiovascular disease (ASCVD) and high Lp(a). The Phase 2 ALPACAR-360 study, presented at the American Heart Association (AHA) Scientific Sessions 2024 and published in JAMA, demonstrated that zerlasiran achieved greater than 80% mean time-averaged placebo-adjusted reductions from baseline in Lp(a) concentrations over 36 weeks.
The study evaluated different dosing regimens of zerlasiran (300 mg every 16 weeks, 300 mg every 24 weeks, or 450 mg every 24 weeks) in patients with Lp(a) levels ≥125 nmol/L. Time-averaged Lp(a) analyses, a novel approach in this study, provided a more accurate assessment of treatment effects over time, including intervals between doses. Maximum Lp(a) reductions exceeded 90%.
Sustained Reductions and Safety
Notably, the reductions in Lp(a) persisted at the final visit, 60 weeks after the initial drug administration, indicating a sustained effect with infrequent dosing. Furthermore, no new safety concerns emerged during the study period.
Steven E. Nissen, MD, Chief Academic Officer of the Heart, Vascular and Thoracic Institute at Cleveland Clinic and the study’s lead author, stated, "These data provide additional information to select the best dose and dosing interval for future zerlasiran Phase 3 trials. 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."
Implications for Future Treatment
The results of the ALPACAR-360 study suggest that zerlasiran has the potential to provide long-term reductions in Lp(a) with infrequent dosing, addressing a significant unmet need in patients with elevated Lp(a) and ASCVD. Silence Therapeutics plans to advance zerlasiran into Phase 3 trials to further evaluate its efficacy and safety as a potential new treatment option.
Curtis Rambaran, MD, Chief Medical Officer at Silence, commented, "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... 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)."
