Zerlasiran Shows Significant Lipoprotein(a) Reduction in Phase 2 Trial

Zerlasiran (Silence Therapeutics) produced greater than 80% reductions in time-averaged lipoprotein(a) (Lp[a]) concentrations in patients with atherosclerotic cardiovascular disease (ASCVD), according to data from a phase 2 assessment of Lipoprotein(a) lowering in cardiovascular disease with SLN360 in the ALPACAR-360 trial (NCT05537571). The findings, published in JAMA Network, support the continued development and investigation of zerlasiran in phase 3 trials.^1,2

Cholesterol buildup and blood cells | Image Credit: © VRAYVENUS - stock.adobe.com

Lp(a) is genetically inherited type of lipoprotein made in the liver and elevated levels are associated with an increased risk of ASCVD. Its structure is similar to low-density lipoprotein (LDL), consisting of an LDL particle which contains apolipoprotein B connected to apolipoprotein A. According to the American Heart Association, approximately 1 in 5 people worldwide have high Lp(a) levels.³

Zerlasiran is a short interfering RNA (siRNA) in development for the treatment of patients with elevated Lp(a). It is a gene “silencing” therapy intended to block the LPA gene, which signals the body to produce Lp(a). Blocking this gene leads to reduced production of Lp(a), thereby lowering ASCVD risk. In a multi-center, randomized, double-blind, placebo-controlled, phase 2 study, zerlasiran was associated with statistically significant reductions in Lp(a) levels.^2,4

ALPACAR-360 evaluated 178 patients ages 18 to 80 years with ASCVD defined as previously with stable ASCVD with serum lipoprotein(a) concentrations greater than or equal to 125 nmol per liter. The enrolled participants were aged 18 to 80 years with ASCVD characterized as myocardial infarction, stroke, angiographically documented coronary artery disease or peripheral arterial disease. To qualify for the trial, the patients had to have stable ASCVD with serum lipoprotein(a) concentrations greater than or equal to 125 nmol/L.²

The patients were randomized to receive a subcutaneous dose of placebo every 16 weeks for 3 doses (n = 23) or every 24 weeks for 2 doses (n = 24) or zerlasiran 450 mg every 24 weeks for 2 doses (n = 45), 300 mg every 16 weeks for 3 doses (n = 42), or 300 mg every 24 weeks for 2 doses (n = 44). The primary end point was the time-averaged percent change in Lp(a) concentration from baseline to 36 weeks.²

Compared with patients in the placebo arm, those receiving zerlasiran experienced time-averaged percent changes at week 36 of −85.6% at the 450 mg dose every 24 weeks (95% CI, −90.9% to −80.3%), −82.8% at the 300 mg dose every 16 weeks (95% CI, −88.2% to −77.4%), and −81.3% at the 300 mg dose every 24 weeks (95% CI, −86.7% to −76.0%). Additionally, zerlasiran was associated with median percent changes in Lp(a) levels of −94.5% (−97.3% to −84.2%) for the 450 mg every 24 weeks group, −96.4% (−97.7% to −92.3%) for the 300 mg every 16 weeks group, and −90.0% (−93.7% to −81.3%) for the 300 mg every 24 weeks group, at week 36.²

Injection site reactions were the most common treatment-related adverse effect (AE) with mild pain occurring in 2.3% to 7.1% of participants on the first day after receiving zerlasiran. Other recorded AEs were considered unrelated to the agent.²

The data suggests zerlasiran is an efficacious and safe therapeutic option to reduce Lp(a) concentrations in affected individuals. Further trials are needed to determine the effect of the drug in larger populations; for example, the study enrolled predominantly White, male participants, excluding racial and ethnic minority populations. However, these initial results show promise and pave the way for continued study into zerlasiran.

REFERENCES

1. Evaluate sln360 in participants with elevated lipoprotein(a) at high risk of atherosclerotic cardiovascular disease events. ClinicalTrials.gov Identifier: NCT05537571. Updated July 31, 2024. Accessed November 25, 2024. https://clinicaltrials.gov/study/NCT05537571

2. Missen S, Wang Q, Nicholls S, et al. Zerlasiran—a small-interfering rna targeting lipoprotein(a), a phase 2 randomized clinical trial. Jama. November 18, 2024. doi:10.1001/jama.2024.21957

3. Lipoprotein (a). American Heart Association. Accessed November 25, 2024. https://www.heart.org/en/health-topics/cholesterol/genetic-conditions/lipoprotein-a

4. Zerlasiran. Silence Therapeutics. Accessed November 25, 2024. https://silence-therapeutics.com/our-pipeline/zerlasiran/default.aspx