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Synthetic Double-Stranded Sirna Oligonucleotide Directed Against Apolipoprotein C-Iii Mrna And Covalently Linked To A Ligand Containing Three N-Acetylgalactosamine Residues

This article summarizes several clinical trials investigating the use of plozasiran, also known as ARO-APOC3, for treating hypertriglyceridemia. Plozasiran is a novel drug that targets apolipoprotein C-III mRNA to reduce triglyceride levels in the blood. The trials aim to evaluate the safety and efficacy of plozasiran in patients with varying degrees of hypertriglyceridemia, including severe cases and those with familial chylomicronemia syndrome.

Table of Contents

What is Plozasiran?

Plozasiran, also known as ARO-APOC3, is a new medication being developed to treat high levels of triglycerides in the blood[1]. It is a type of drug called a synthetic double-stranded siRNA oligonucleotide. This means it’s a small piece of genetic material designed to interfere with the production of a specific protein in the body[2].

How Does Plozasiran Work?

Plozasiran works by targeting a protein called apolipoprotein C-III (APOC3). This protein plays a role in regulating triglyceride levels in the blood. By reducing the production of APOC3, plozasiran aims to lower triglyceride levels[3].

The drug is designed with a special feature: it’s attached to a molecule containing three N-acetylgalactosamine residues. This helps the drug target liver cells specifically, where it can have the most impact on triglyceride metabolism[4].

Medical Conditions Treated

Plozasiran is being studied for the treatment of several conditions related to high triglyceride levels:

  • Severe Hypertriglyceridemia (SHTG): This is a condition where triglyceride levels in the blood are very high (500 mg/dL or more)[1].
  • Mixed Dyslipidemia: This condition involves abnormal levels of multiple types of fats (lipids) in the blood, including triglycerides[4].
  • Familial Chylomicronemia Syndrome (FCS): This is a rare genetic disorder that causes extremely high triglyceride levels[5].

Clinical Trials

Plozasiran is currently being studied in several clinical trials:

  • SHASTA-3 and SHASTA-4: These are Phase 3 trials for adults with severe hypertriglyceridemia[1].
  • MUIR-3: This is a Phase 3 trial for adults with hypertriglyceridemia[3].
  • A Phase 2 open-label extension study for adults with dyslipidemia[4].
  • A Phase 3 study for adults with Familial Chylomicronemia Syndrome[5].

Administration and Dosage

Plozasiran is administered as a subcutaneous injection, which means it’s injected under the skin. The drug comes in a pre-filled syringe for ease of use[1].

In clinical trials, the maximum daily dose being studied is 25-50 mg, with a total treatment period of up to 12 months[5].

Efficacy

The main goal of plozasiran treatment is to reduce triglyceride levels in the blood. In clinical trials, researchers are measuring:

  • Percent change in fasting triglyceride levels from the start of treatment to various time points[1].
  • The proportion of patients who achieve triglyceride levels below certain thresholds (e.g., below 500 mg/dL or below 150 mg/dL)[2].
  • Changes in other lipid measurements, such as non-HDL cholesterol and apolipoprotein B levels[4].

Safety and Side Effects

As with any new medication, researchers are carefully monitoring the safety of plozasiran. Some key safety considerations include:

  • Monitoring liver function tests (ALT and AST levels)[5].
  • Checking HbA1c levels, which reflect blood sugar control[1].
  • Watching for any signs of pancreatitis, a potential complication of very high triglyceride levels[2].

The full range of potential side effects is still being studied in ongoing clinical trials.

Ongoing Research

Research on plozasiran is ongoing, with several clinical trials in progress. These studies will help determine the long-term safety and effectiveness of the drug for different patient groups[4].

It’s important to note that while the results so far are promising, plozasiran is still an investigational drug. It has not yet been approved by regulatory agencies for general use. Patients interested in this treatment should speak with their healthcare provider about the possibility of participating in clinical trials[5].

Trial Name Condition Primary Endpoint Key Inclusion Criteria Duration
SHASTA-3 Severe Hypertriglyceridemia Percent change in fasting serum TG levels from baseline to Month 12 Fasting TG ≥500 mg/dL 12 months
SHASTA-4 Severe Hypertriglyceridemia Percent change in fasting serum TG levels from baseline to Month 12 Fasting TG ≥500 mg/dL 12 months
MUIR-3 Hypertriglyceridemia Percent change in fasting serum TG levels from baseline to Month 12 Fasting TG 150-499 mg/dL 12 months
Open-Label Extension Mixed Dyslipidemia Subject incidence of treatment-emergent adverse events Completed parent study Up to 104 weeks
FCS Study Familial Chylomicronemia Syndrome Percent change from baseline at Month 10 in fasting TG Fasting TG ≥880 mg/dL, FCS diagnosis 36 months

FAQ

  • What is plozasiran and how does it work? Plozasiran, also known as ARO-APOC3, is a synthetic double-stranded siRNA oligonucleotide that targets apolipoprotein C-III mRNA. It is designed to reduce triglyceride levels in the blood by decreasing the production of apolipoprotein C-III, which plays a role in triglyceride metabolism.
  • What conditions are being studied in these clinical trials? The clinical trials are investigating plozasiran for treating various forms of hypertriglyceridemia, including severe hypertriglyceridemia (SHTG), mixed dyslipidemia, and familial chylomicronemia syndrome (FCS).
  • How is plozasiran administered? Plozasiran is administered as a subcutaneous injection, typically using a pre-filled syringe.
  • What are the main goals of these clinical trials? The main goals of these trials are to evaluate the efficacy of plozasiran in reducing triglyceride levels, assess its safety profile, and determine the proportion of patients who achieve target triglyceride levels after treatment.
  • How long do these clinical trials last? The duration of the trials varies, but most of them last for 12 months, with some extending up to 36 months for long-term safety and efficacy evaluation.

Ongoing Clinical Trials on Synthetic Double-Stranded Sirna Oligonucleotide Directed Against Apolipoprotein C-Iii Mrna And Covalently Linked To A Ligand Containing Three N-Acetylgalactosamine Residues

  • Study of Plozasiran to prevent acute pancreatitis in adults with severe hypertriglyceridemia

    Recruiting

    3 1
    Investigated diseases:
    Investigated drugs:
    Austria Belgium Bulgaria Hungary Latvia Lithuania +3

  • Long-Term Safety Study of Plozasiran for Adults with High Triglycerides

    Recruiting

    3 1 1
    Investigated drugs:
    Belgium Bulgaria Croatia Czechia France Germany +8

  • Study on Plozasiran and ARO-APOC3 for Adults with Severe Hypertriglyceridemia

    Not recruiting

    3 1
    Investigated drugs:
    Bulgaria Czechia France Germany Hungary Latvia +4

  • Study of Plozasiran for Adults with Severe Hypertriglyceridemia

    Not recruiting

    3 1
    Investigated drugs:
    Belgium Bulgaria Croatia Czechia Hungary Italy +4

  • Study on the Effects of ARO-APOC3 for Adults with Familial Chylomicronemia Syndrome

    Not recruiting

    3 1
    Investigated drugs:
    Austria Belgium Croatia France Ireland Poland +1

  • Study to Evaluate Plozasiran for Adults with High Triglycerides

    Not recruiting

    3 1
    Investigated drugs:
    Bulgaria Czechia France Germany Hungary Italy +3

  • Study on Long-Term Safety and Efficacy of ARO-APOC3 for Adults with Mixed Dyslipidemia

    Not recruiting

    2 1 1
    Investigated drugs:
    Hungary The Netherlands Poland

Glossary

  • Hypertriglyceridemia: A condition characterized by elevated levels of triglycerides in the blood, which can increase the risk of heart disease and pancreatitis.
  • Severe Hypertriglyceridemia (SHTG): A more serious form of hypertriglyceridemia, typically defined as triglyceride levels of 500 mg/dL or higher.
  • Familial Chylomicronemia Syndrome (FCS): A rare genetic disorder that causes extremely high levels of triglycerides in the blood, leading to recurrent episodes of pancreatitis.
  • siRNA: Small interfering RNA, a type of molecule that can be used to silence specific genes and reduce the production of certain proteins.
  • Apolipoprotein C-III: A protein involved in triglyceride metabolism; high levels of this protein can lead to elevated triglycerides in the blood.
  • Triglycerides: A type of fat found in the blood that is used for energy storage; high levels can increase the risk of heart disease and pancreatitis.
  • LDL-C: Low-density lipoprotein cholesterol, often referred to as 'bad' cholesterol, which can contribute to the buildup of plaque in arteries.
  • HDL-C: High-density lipoprotein cholesterol, often called 'good' cholesterol, which helps remove other forms of cholesterol from the bloodstream.
  • HbA1c: Hemoglobin A1c, a measure of average blood sugar levels over the past 2-3 months, used to diagnose and monitor diabetes.
  • Pancreatitis: Inflammation of the pancreas, which can be caused by very high levels of triglycerides in the blood.

References

  1. http://clinicaltrials.eu/trial/study-of-plozasiran-for-adults-with-severe-hypertriglyceridemia/
  2. http://clinicaltrials.eu/trial/study-on-plozasiran-and-aro-apoc3-for-adults-with-severe-hypertriglyceridemia/
  3. http://clinicaltrials.eu/trial/study-to-evaluate-plozasiran-for-adults-with-high-triglycerides/
  4. http://clinicaltrials.eu/trial/study-on-long-term-safety-and-efficacy-of-aro-apoc3-for-adults-with-mixed-dyslipidemia/
  5. http://clinicaltrials.eu/trial/study-on-the-effects-of-aro-apoc3-for-adults-with-familial-chylomicronemia-syndrome/