Zerlasiran Leads to Significant Lipoprotein(a) Reductions at 36 Weeks

Silence Therapeutics has released promising findings from the ongoing ALPACAR-360 phase 2 trial of zerlasiran, demonstrating a 90% median decrease in lipoprotein(a) (Lp[a]) at week 36.

The study involved 178 participants with baseline Lp(a) levels of 125 nmol/L or higher, putting them at significant risk for atherosclerotic cardiovascular disease (ASCVD) events. Zerlasiran, a short interfering RNA (siRNA), aims to reduce the body's production of Lp(a), a crucial genetic risk factor for cardiovascular issues affecting a substantial portion of the global population.

According to a news release from the London-based pharmaceutical company, the results showed a highly significant decrease from the initial levels of Lp(a) compared with the placebo at the 36-week mark, meeting the primary endpoint of the study.¹ During the double-blind placebo-controlled treatment phase, zerlasiran was delivered subcutaneously at doses of 300 mg every 16 or 24 weeks, and 450 mg every 24 weeks, to individuals with a median baseline Lp(a) level of around 215 nmol/L. Both dosage groups experienced a median reduction in Lp(a) of 90% or more by week 36. Importantly, no additional safety issues were detected during this phase of treatment.

“We are excited about the emerging phase 2 data, which are very consistent with phase 1 results and support a competitive profile for treating patients with high Lp(a),” said Steven Romano, MD, head of research and development at Silence Therapeutics. “We look forward to reviewing the 48-week data and advancing zerlasiran as a potential treatment to address this major unmet need in cardiovascular disease.”

Zerlasiran is wholly owned by Silence Therapeutics and works as a gene silencing therapy, aiming to temporarily stop the transmission of a particular gene's instructions that could lead to undesired outcomes. According to the Silence Therapeutics website, the siRNA targets the LPA gene responsible for prompting the body to produce a protein unique to Lp(a).² By suppressing the LPA gene, zerlasiran reduces Lp(a) levels, with the intention of diminishing the likelihood of heart diseases, heart attacks, and strokes.

Silence Therapeutics wrapped up phase 1 of the study in August 2023 with 70 participants. In the Phase 1 APOLLO single-dose study, patients with high Lp(a) levels (≥150 nmol/L) who received zerlasiran 300 mg and 600 mg doses experienced median maximal reductions in Lp(a) of 96% and 98%, respectively.³ Throughout 150 days of follow-up, both dosage groups showed median time-averaged reductions exceeding 80% in Lp(a). The treatment was well tolerated with no serious safety concerns reported.

The 60-week ALPACAR-360 study is ongoing, and secondary endpoints will be assessed. These include examining changes in Lp(a) levels from baseline to 48 weeks (end of treatment period) and 60 weeks (end of the study), as well as assessing potential effects on other lipids/lipoproteins. Following these positive 36-week results, Silence Therapeutics plans to announce 48-week results of the ongoing ALPACAR-360 study in the second quarter of 2024.

References

1. Silence Therapeutics announces positive topline 36-week data from ongoing phase 2 study of zerlasiran in patients with high lipoprotein(a). News release. Silence Therapeutics. March 13, 2024. Accessed March 13, 2024. https://silence-therapeutics.com/investors/press-releases/press-releases-details/2024/Silence-Therapeutics-Announces-Positive-Topline-36-Week-Data-from-Ongoing-Phase-2-Study-of-Zerlasiran-in-Patients-with-High-Lipoproteina/default.aspx

2. Addressing a major unmet need in cardiovascular disease. Silence Therapeutics. Accessed March 13, 2024. https://silence-therapeutics.com/our-pipeline/zerlasiran/default.aspx

3. Silence Therapeutics completes enrollment in phase 2 study of zerlasiran (SLN360) in subjects with elevated lipoprotein(a) at high risk of atherosclerotic cardiovascular disease events. News release. Silence Therapeutics. May 1, 2023. Accessed March 13, 2024. https://silence-therapeutics.com/investors/press-releases/press-releases-details/2023/Silence-Therapeutics-Completes-Enrollment-in-Phase-2-Study-of-Zerlasiran-SLN360-in-Subjects-with-Elevated-Lipoproteina-at-High-Risk-of-Atherosclerotic-Cardiovascular-Disease-Events/default.aspx