A Phase 2 trial of zerlasiran, a small interfering RNA (siRNA), has demonstrated cumulative reductions in elevated lipoprotein(a) [Lp(a)] levels with successive doses. The ALPACAR-360 trial showed that zerlasiran reduced time-averaged Lp(a) concentrations by more than 80% across 36 weeks of treatment, marking a significant step forward in addressing this genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD).
Novel Endpoint Shows Treatment Effect Over Time
The study, presented at the American Heart Association Scientific Sessions 2024, used a distinctive endpoint: time-averaged percentage change in serum Lp(a) from baseline through 36 weeks. This approach, according to Steven Nissen, MD, Chief Academic Officer of Cleveland Clinic’s Heart, Vascular and Thoracic Institute, more accurately reflects the effect of treatment over time, including intervals between doses. The trial involved 180 adults with stable ASCVD and Lp(a) concentrations of at least 125 nmol/L, a threshold indicating increased cardiovascular risk.
Study Design and Key Findings
Patients were randomized to receive either placebo or zerlasiran (300 mg every 16 weeks, 300 mg every 24 weeks, or 450 mg every 24 weeks). The results indicated substantial reductions in Lp(a) concentrations compared to placebo:
- -85.6% with 450 mg every 24 weeks (95% CI, -90.9% to -80.3%)
- -82.8% with 300 mg every 16 weeks (95% CI, -88.2% to -77.4%)
- -81.3% with 300 mg every 24 weeks (95% CI, -86.7% to -76.0%)
Notably, the median reduction at the 60-week final follow-up visit was still 58.8% in the group that received three doses of zerlasiran 300 mg, 28 weeks after the last dose. This cumulative effect informs the dosing interval for Phase 3 studies.
Safety and Tolerability
Injection-site reactions were the most common treatment-related adverse effects, with mild pain reported by 2.3% to 7.1% of participants. No such reactions led to study withdrawal or missed doses, and no treatment-related serious adverse events occurred.
Implications for Future Research
The findings suggest that zerlasiran holds promise for reducing Lp(a), a risk factor resistant to traditional therapies like statins. The cumulative effect observed with successive doses will inform the dosing interval chosen for phase 3 studies of zerlasiran. According to Dr. Nissen, the consistent responses to therapy with zerlasiran 300 mg dosed every 16 weeks suggest that this regimen may provide more uniformly substantial reduction across all patients compared with dosing every 24 weeks.
Addressing Unmet Needs in ASCVD
Elevated Lp(a) is a genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD) that is resistant to traditional preventive therapies, including statins. Currently, no pharmacotherapies have been approved for Lp(a) reduction, making the development of effective treatments like zerlasiran crucial.
