zerlasiran lowers lipoprotein (a) by up to 90% after 8 months

Zerlasiran, an RNA-based treatment, lowers lipoprotein (a) levels by more than 90% after an 8-month period, according to the results of a phase 2 study published by Silence Therapeutics. It could represent a new therapeutic class for patients at increased risk of atherosclerotic cardiovascular events (ASCVD).

About 25% of the population has high levels of Lp(a), which increase the risk of cardiovascular disease, independent of other factors. Plasma levels of Lp(a) are genetically determined, the main gene involved being LPA. Zerlasiran is an agent siRNA (short interfering RNA) or a therapy of gene silencing, designed to reduce Lp(a) production. It exerts its action by blocking the LPA gene that codes for alipoprotein(a), a component of Lp(a).

Biotech company Silence Therapeutics achieved promising results in the 36-week phase 2 (ALPACAR-360) study of Zerlasiran (primary objective).

Phase 2 of the study consisted of a double-blind placebo-controlled treatment administered to a group of 178 patients at increased risk of ASCVD, who had Lp(a) levels ≥ 125 nmol/L (baseline median value being 215 nmol/L). Zerlasian was administered subcutaneously at a dose of 300 mg every 16 or 24 weeks and at a dose of 450 mg every 24 weeks. The mean percent reduction in Lp(a) values ​​for both doses administered was ≥ 90% at week 36. Also, no significant adverse effects were observed during the monitoring period.

The 60-week study is ongoing. Secondary outcome assessment will include the change in Lp(a) levels from baseline to week 48 (end of treatment phase) and to week 60 (end of study). Moreover, the study will also take into account the impact on other types of lipids and lipoproteins.

Previous, phase 1 demonstrated that treatment with varying doses (30 mg-600 mg) administered subcutaneously reduced plasma Lp(a) levels for 45-60 days in a dose-dependent manner.

Silence Therapeutics plans to report data for the 48 weeks in the second quarter of this year.

Lp(a) is a particle that resembles LDL-C, but includes an additional protein called apolipoprotein (a). This structural difference makes Lp(a) more atherogenic, meaning it is more likely to contribute to the formation of fatty deposits in the arteries. Lp(a) is also involved in thrombosis mechanisms, further increasing the risk of acute cardiovascular events. Despite its importance, Lp(a) is not routinely tested. The European Society for the Study of Atherosclerosis (EAS) and the Society of Cardiology (ESC) recommend once-in-a-lifetime lp(a) testing in all adults.

RNA interference (RNAi) is a biological process by which RNA molecules inhibit gene expression. It is an essential mechanism for regulating gene activity and has significant potential for therapeutic applications. The role of RNA-based therapies in treating people with elevated lipoprotein(a) levels involves using RNAi technology to target and reduce the production of Lp(a) in the liver, where it is synthesized. Thus, small interfering RNA (siRNA) molecules are being developed that target the messenger RNA encoding apolipoprotein (a) and decrease the synthesis of Lp(a), reducing its levels in the blood. This approach may help reduce the risk of cardiovascular disease associated with high Lp(a) levels.

Several RNAi therapies are in development or in clinical trials to treat people with elevated levels of lipoprotein (a) and other diseases caused by the overexpression of certain proteins. These therapies offer a promising new approach to treating diseases that are difficult to manage with traditional drugs, including genetic disorders and various forms of cancer. By specifically targeting the genetic basis of these diseases, RNA-based therapies may represent more effective and personalized treatment options.

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