Plozasiran

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Created On: 24/03/2026

Plozasiran is an Food and Drug Administration (FDA) approved small interfering RNA (siRNA) developed for the treatment of familial chylomicronemia syndrome (FCS), a rare inherited disorder caused by autosomal recessive defects, leading to extremely high triglyceride (TG) levels and a high risk of acute pancreatitis.

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Introduction

Key clinical relevance

In FCS, TG levels often exceed 1,000 mg/dL (range of 1500 to 15 000 mg/dL) with a high risk of recurrent acute pancreatitis.[3] Plozasiran offers a targeted molecular approach to considerably diminish TG levels and pancreatitis risk in the affected patients.[4]

Pharmacological class: Small interfering RNA (siRNA) therapeutic, more specifically apolipoprotein C-III (APOC-III) inhibitor

Indications

It is used as an adjunct to diet to decrease TG levels in FCS.[1]

Pharmachologic action

FCS is a rare genetic disorder caused by deficient or impaired lipoprotein lipase (LPL) activity, leading to severe hypertriglyceridemia and a high risk of acute pancreatitis. APOC3 plays a key role in regulating TG-rich lipoprotein metabolism via both LPL-dependent and independent pathways.[4]

Plozasiran is a double-stranded siRNA molecule conjugated with N-acetylgalactosamine (GalNAc), a targeting ligand that directs the drug specifically to hepatocytes in the liver.

Targeted hepatic uptake: The GalNAc component binds to receptors on liver cells, allowing selective delivery of the siRNA into hepatocytes.
Activation of RNA interference pathway: Once inside the cell, plozasiran is incorporated into the RNA-induced silencing complex (RISC), a cellular machinery responsible for gene silencing.
Selective mRNA degradation: The RISC-loaded siRNA recognizes and binds to APOC3 messenger RNA (mRNA). This interaction triggers enzymatic cleavage and destruction of the APOC3 mRNA, preventing its translation into the APOC3 protein.
Restoration of TG Metabolism: With APOC3 levels reduced:

Lipoprotein lipase activity increases
Hepatic clearance of TG-rich lipoproteins improves
Circulating chylomicrons and very-low-density lipoprotein (VLDL) decrease[5]

Dosage

Recommended dose

The standard dose of plozasiran is 25 mg given as a subcutaneous injection once every 3 months. This extended dosing interval supports sustained suppression of APOC3 and long-term control of TG levels.

Dosage form

Injection: 25 mg / 0.5 mL plozasiran supplied as a clear, colorless to yellow solution in a single-use prefilled syringe.[1]

Pharmacokinetics

Absorption

Following subcutaneous injection, plozasiran is absorbed into the systemic circulation with a maximum plasma concentration (Cmax) of approximately 68.5 ng/mL. Peak levels are typically reached at a median time (Tmax) of about 6 hours after administration.

Distribution

At clinically relevant plasma concentrations, about 78% of plozasiran binds to plasma proteins in vitro. With repeated subcutaneous dosing of 25 mg, the estimated apparent volume of distribution is approximately 146 L, suggesting extensive distribution beyond the vascular compartment. Initially, the drug distributes within plasma and extracellular fluid, after which it is taken up by hepatocytes, where it suppresses apoC-III mRNA expression and contributes to reductions in circulating TGs.

Metabolism

The drug undergoes enzymatic degradation by nucleases, resulting in the formation of shorter oligonucleotide fragments of varying lengths.

Elimination

Plozasiran is cleared from plasma with a terminal half-life of roughly 3–4 hours. The mean apparent systemic clearance has been estimated at 33.8 L/hour.

Excretion

A portion of the administered dose is eliminated through the kidneys, with approximately 16–19% of the dose recovered in urine.[5]

Contraindications

None

Drug interaction

None

Side effects

The most common side effects are:

High blood sugar (hyperglycemia)
Headache
Nausea
Injection site reaction (pain, redness, or swelling)[1]

Precautions

Monitor TG levels closely, especially in high-risk conditions like pregnancy, to minimize the risk of acute pancreatitis.
There are no data on its presence in breast milk; although infant exposure is expected to be low, potential risks cannot be ruled out.
Human safety data in pregnant women remains limited, so the drug is mainly recommended only when the expected benefit outweighs potential fetal risk.
Clinical data remains insufficient in those with end-stage renal disease or severe kidney impairment.
Safety information is limited in individuals with moderate to severe hepatic impairment.
In pediatrics, the safety and efficiency have not been established.
Clinical studies did not demonstrate prominent differences in safety or efficacy among patients aged 65 years or older compared with younger adults.[1]

Clinical evidence

1. SHASTA-2 trial (Phase 2b)

The SHASTA-2 trial, a multicentre, randomized, double-blind, placebo-controlled Phase 2b study, evaluated plozasiran in 229 adults (mean age 55 years; 78% male) with severe hypertriglyceridemia (fasting TG 500–4000 mg/dL).
Participants received two subcutaneous doses (10, 25, or 50 mg) or placebo (day 1 and week 12) and were followed through week 48.
The key outcome was the percent alteration in fasting TG levels at week 24.
Treatment produced dose-dependent lipid improvements, with the 50-mg dose achieving up to a 57% placebo-adjusted reduction in TGs, along with an approximate 77% reduction in APOC3 levels.
Importantly, 90.6% of treated patients achieved TG levels below 500 mg/dL, a clinically relevant threshold associated with reduced pancreatitis risk.
Additional lipid benefits included reductions in remnant cholesterol and VLDL concentrations, as well as an increase in high-density lipoprotein cholesterol (HDL-C).
The therapy illustrated a favorable safety profile, with adverse event rates same to placebo. Most reported events were mild to moderate supporting the clinical potential of APOC3 inhibition for the management of severe hypertriglyceridemia.[6]

2. PALISADE trial

In a phase 3 global trial (PALISADE), 75 patients with fasting TG ≥880 mg/dL on stable therapy received plozasiran (25 or 50 mg) or placebo for 12 months, followed by a 2-year open-label extension (OLE) with plozasiran 25 mg.
Among 65 patients entering the OLE, baseline TGs were ~2103 mg/dL, and treatment led to sustained reductions of −76% at 24 months, lowering levels to ~444 mg/dL, with similar benefits in both early and crossover groups.
These improvements were accompanied by −89% reductions in APOC3, increases in HDL-C (+66%), and reductions in non-HDL-C (−37%) and VLDL-C (−56%), while LDL-C rose modestly but remained low and ApoB levels stayed within safe ranges.
Clinically, 42% of patients attained TG <500 mg/dL and 66% <880 mg/dL, indicating meaningful risk reduction thresholds for pancreatitis.
Plozasiran demonstrated a consistent and favorable safety profile, with low discontinuation rates and adverse events similar to earlier phases, most commonly abdominal pain, nasopharyngitis, headache, nausea, and COVID-19, while HbA1c remained stable.
Overall, plozasiran shows deep, durable TG and APOC3 reduction with sustained efficacy and good tolerability, supporting its potential as a promising long-term therapy for FCS.[7]

References

1. REDEMPLO (plozasiran) injection. FDA label. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/219947s000lbl.pdf
2. Hang S, Hegele RA. The evaluation of plozasiran for the treatment of familial chylomicronemia syndrome. Expert Review of Endocrinology & Metabolism. 2026 Mar 20:1-10.
3. Gouni-Berthold I. Significant Quality of Life Improvement Observed in a Patient With FCS Associated With a Marked Reduction in Triglycerides. Journal of the Endocrine Society. 2019 Dec 23;4(2):bvz035.
4. Watts GF, Rosenson RS, Hegele RA, Goldberg IJ, Gallo A, Mertens A et al. Plozasiran for Managing Persistent Chylomicronemia and Pancreatitis Risk. New England Journal of Medicine. 2025 Jan 9;392(2):127-137.
5. Plozasiran. Drug Bank [DB18997]. Available from: https://go.drugbank.com/drugs/DB18997
6. Gaudet D, Pall D, Watts GF, Nicholls SJ, Rosenson RS, Modesto K et al. Plozasiran (ARO-APOC3) for Severe Hypertriglyceridemia: The SHASTA-2 Randomized Clinical Trial. JAMA Cardiology. 2024 Jul 1;9(7):620-630.
7. Watts G, Rosenson RS, Hegele RA, Goldberg IJ, Gallo A, Mertens A et al. A randomized, placebo-controlled phase 3 study of plozasiran in patients with familial chylomicronemia syndrome: PALISADE-1 year open label extension. European Heart Journal. 2025 Nov;46(Supplement_1):ehaf784-3969.