RNA interference agent plozasiran targets APOC3 for effective mixed hyperlipidemia treatment

By Dr. Liji Thomas, MDReviewed by Benedette Cuffari, M.Sc.May 31 2024

In a recent study published in The New England Journal of Medicine, researchers evaluate the efficacy of plazosiran treatment on fasting triglyceride levels in adult patients with mixed hyperlipidemia (MH).

Study: Plozasiran, an RNA interference agent targeting APOC3, for mixed hyperlipidemia. Image Credit: peterschreiber.media / Shutterstock.com

The role of lipoproteins in cardiovascular diseases

MH is a condition in which unhealthy fats in the blood are raised in a specific pattern. People with MH are at a greater risk for atherosclerosis, during which plaques of fatty acids, cholesterol, and calcium accumulate within the arteries. This can both increase blood pressure levels and prevent blood flow to the heart, thereby causing coronary heart disease (CHD), stroke, or peripheral arterial disease.

Lipoproteins in the blood carry fats in various directions. Triglyceride-rich lipoproteins include chylomicrons, chylomicron remnants, very-low-density lipoproteins (VLDLs), as well as VLDL remnants, such as intermediate-density lipoproteins (IDLs), all of which have up to four times higher cholesterol density than low-density lipoproteins (LDL) and are often associated with an increased risk of CHD. Thus, triglyceride levels are a useful representative marker for these other lipoproteins.

Like LDL cholesterol, remnant cholesterol from triglyceride-rich lipoproteins (TRL-cholesterol) contribute to plaque formation. Although current LDL cholesterol-lowering agents can successfully reduce the risk of CHD in MH, they do not reduce triglyceride or remnant cholesterol levels.

In fact, multiple trials reviewed in a recent meta-analysis found that non-HDL cholesterol was the single largest marker for major adverse cardiovascular events (MACE). Non-HDL cholesterol includes LDL, lipoprotein[a], and TRL. Yet, triglyceride-lowering agents that reduced triglyceride levels have not been associated with a reduced risk of MACE.

What is plazosiran?

These limitations of traditional cholesterol treatments have led researchers to investigate the potential of drugs that may enhance the clearance of TRL. One such pathway involves apolipoprotein C3 (APOC3), a liver glycoprotein found on all lipoproteins.

APOC3 inhibits lipoprotein lipase, which breaks down lipoprotein, thereby increasing TRL levels by preventing its degradation and subsequent uptake into liver cells. Suppression of APOC3 has been associated with reduced levels of triglycerides and remnant cholesterol and, as a result, a 40% reduction in CHD risk.

One potential drug that could downregulate APOC3 is plazosiran, which is a small interfering ribonucleic acid (RNA) agent that targets APOC3 within hepatocytes. Plazosiran has been shown to be highly specific and potent with limited associated side effects.

Previously, researchers have demonstrated that plazosiran treatment leads to a significant, sustained, and dose-dependent reduction in triglyceride and APOC3 levels in both healthy individuals and those with high triglyceride levels of 300 mg/dL or more.

About the study

The current study discusses the results of a double-blinded phase IIb randomized controlled trial (RCT) that assessed the safety and efficacy of plazosiran. The target population comprised 353 patients with MH, with a mean age of 61 years and mean body mass index (BMI) value of 32. About 60% of the study cohort were diabetic, whereas 12% had a 10-year risk for cardiovascular disease of over 20%.

The average triglyceride and fasting LDL levels were 244 mg/dL and 103 mg/dL, respectively, whereas the average non-HDL and remnant cholesterol levels were 151 mg/dL and 47 mg/dL, respectively.

About 92% of patients were currently receiving statins, 54% of whom were receiving high-intensity statins. Other cholesterol-lowering agents were used by 2-14% of participants.

Study participants were assigned to recieve plazosiran or placebo in a 3:1 ratio. In three cohorts, either placebo or plazosiran was given in three doses subcutaneously at dosages of 10, 25, or 50 m, on day one and week 12. In the fourth cohort, 50 mg of plazosiran or placebo was administered on day one and week 24.

What did plazosiran do to triglyceride levels?

Plazosiran recipients exhibited a difference from baseline of nearly 50 percentage points with the lowest dose to 62 percentage points with the highest quarterly dose as compared to placebo. With the half-yearly dosage, the difference was by 44 percentage points.

APOC3 levels also showed corresponding changes, with the plazosiran group exhibiting differences between 58-80% from baseline as compared to the placebo group. Other lipoproteins, including non-HDL levels, were also reduced, which was mainly due to changes in remnant cholesterol levels.

Apolipoprotein B (apoB) levels also declined with plazosiran treatment, irrespective of the initial triglyceride levels. In contrast, patients with the highest triglyceride levels at baseline exhibited a small increase in LDL levels with the two lowest doses of plazosiran. However, since their baseline non-HDL and remnant cholesterol was the highest among all participants, they had a greater reduction in both non-HDL and remnant cholesterol in absolute terms as compared with other tertiles of triglyceride levels.

The effects of plazosiran continued to be observed at week 48. No significant differences in adverse effects were observed between the groups, except for glycemic control.

Blood sugar levels rose in approximately 10% of all participants who received the placebo treatment, as well as 12% and 7% of the quarterly 10 mg and 25 mg plazosiran recipients, respectively. Comparatively, 20% and 21% of quarterly and half-yearly 50 mg plazosiran recipients, respectively, experienced worsened glycemic control.

Conclusions

Patients with MH benefited from plazosiran treatment, as demonstrated by lowered triglyceride levels by 24 weeks from treatment initiation. Previous research has established that reducing LDL cholesterol leads to reductions in both non-HDL cholesterol and apoB. However, the current study findings suggest that the reduction in non-HLD levels observed with statins and other similar drugs may due to declining remnant cholesterol levels, rather than LDL.

The rise in blood sugar may be due to increased liver activity. Importantly, this adverse effect can be easily treated and should not outweigh the potential benefits of this treatment.  

This trial has helped in laying the groundwork for a more extensive outcomes trial, which would more rigorously test whether plozasiran reduces levels of non-HDL cholesterol and cholesterol remnants and the risk of atherosclerotic cardiovascular disease.”