Zerlasiran Achieves Over 80 Percent Reduction in Lipoprotein(a) Levels in ASCVD Patients: Phase 2 Trial Results

The findings, published in the Journal of the American Medical Association (JAMA), revealed that zerlasiran demonstrated a favorable safety profile and achieved a reduction of over 80% in time-averaged lipoprotein(a) levels during 36 weeks of treatment in patients with atherosclerotic cardiovascular disease (ASCVD).

Elevated Lp(a) levels are increasingly recognized as an independent cardiovascular risk factor linked to conditions such as coronary artery disease, stroke, and peripheral arterial disease. However, current therapeutic options for targeting Lp(a) specifically remain limited.

Zerlasiran, designed to inhibit LPA gene expression—responsible for Lp(a) production—was administered via subcutaneous injections at varying dosages. Its targeted mechanism of action represents a significant leap forward, addressing an unmet need for patients with high Lp(a) levels. Considering this, Steven E. Nissen, Cleveland Clinic Coordinating Center for Clinical Research, Cleveland, Ohio, and colleagues aimed to assess the impact of Zerlasiran, a small-interfering RNA designed to target hepatic production of apolipoprotein(a), on serum lipoprotein(a) levels.

For this purpose, the researchers conducted a multicenter trial involving patients with stable ASCVD and lipoprotein(a) levels ≥125 nmol/L at 26 sites across Europe and South Africa between January 2023 and April 2023, with follow-up until July 2024. Participants received either a placebo or Zerlasiran in varying doses and intervals.

The primary outcome measured was the time-averaged percentage change in lipoprotein(a) levels from baseline to 36 weeks, with extended follow-up to 60 weeks.

The study led to the following findings:

• The study included 178 patients with a mean age of 63.7 years; 25.8% were female.

• The median baseline lipoprotein(a) concentration was 213 nmol/L.

• A total of 172 patients completed the trial.

• Compared to the pooled placebo group, the least-squares mean time-averaged percent change in lipoprotein(a) concentration from baseline to week 36 was:

• −85.6% for the 450 mg every 24 weeks group.

• −82.8% for the 300 mg every 16 weeks group.

• −81.3% for the 300 mg every 24 weeks group.

• The median percent change in lipoprotein(a) concentration at week 36 was:

• −94.5% for the 450 mg every 24 weeks group.

• −96.4% for the 300 mg every 16 weeks group.

• −90.0% for the 300 mg every 24 weeks group.

• Injection site reactions, including mild pain, were the most common treatment-related adverse effects, occurring in 2.3% to 7.1% of participants on the first day after administration.

• There were 20 serious adverse events reported in 17 patients, none of which were related to the study drug.

The findings revealed that Zerlasiran achieved over 80% reductions in time-averaged lipoprotein(a) concentrations over 36 weeks with doses of 300 mg every 16 weeks or 300 mg and 450 mg every 24 weeks. Sustained reductions were observed up to 60 weeks after the initial dose.

"The treatment was well-tolerated, with no safety concerns identified with the infrequent dosing schedule. These results highlight the potential of Zerlasiran and support its progression to Phase 3 clinical trials," the researchers concluded.

Reference:

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