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PEGZILARGINASE

Pegzilarginase is an investigational drug being studied in several clinical trials for the treatment of Arginase 1 Deficiency (ARG1-D), a rare genetic disorder. This condition results from a deficiency of the arginase 1 enzyme, which leads to elevated levels of arginine in the blood and causes neurological problems and mobility issues. Clinical trials are examining how pegzilarginase, administered weekly through subcutaneous (under the skin) or intravenous injections, can help reduce plasma arginine levels and potentially improve mobility and other symptoms in patients with this rare condition. The drug is being studied in various age groups, including infants under 24 months, children, and adults, with promising early results.

Table of Contents

What is Pegzilarginase?

Pegzilarginase (also known as Co-ArgI-PEG, AEB1102, or Loargys) is a medication designed to treat a rare genetic disorder called Arginase 1 Deficiency. This enzyme replacement therapy works by replacing the function of the missing or defective arginase 1 enzyme in patients with this condition.[1]

The medication is being developed to help control high levels of arginine in the blood, which is the primary problem in people with Arginase 1 Deficiency. By breaking down excess arginine, pegzilarginase aims to prevent the toxic buildup of this amino acid and related compounds that can cause serious neurological and physical problems.[2]

What is Arginase 1 Deficiency?

Arginase 1 Deficiency (ARG1-D), also called hyperargininemia, is a rare inherited metabolic disorder. It occurs when the body lacks sufficient amounts of the enzyme arginase 1, which is responsible for breaking down the amino acid arginine as part of the urea cycle.[3]

Without enough of this enzyme, arginine builds up in the blood to toxic levels, leading to a variety of symptoms including:

  • Progressive neurological problems
  • Developmental delays
  • Mobility issues (difficulty walking, running, or jumping)
  • Spasticity (stiff or tight muscles)
  • Seizures
  • Intellectual disability

The current standard treatment for ARG1-D includes individualized disease management (IDM), which typically consists of severe protein restriction in the diet, essential amino acid supplementation, and sometimes ammonia scavenger medications when necessary. However, these approaches often don’t fully control the disease.[2][3]

How is Pegzilarginase Administered?

According to the clinical trials, pegzilarginase can be administered in two ways:

  1. Intravenous (IV) infusion: The medication is given directly into a vein, typically once a week.[3]
  2. Subcutaneous (SC) injection: The medication is injected under the skin, also once weekly. This method is being studied as an alternative to IV administration and may be more convenient for long-term treatment.[1][2]

The clinical trials show that after patients have been on the IV form for some time, they may have the option to switch to subcutaneous administration, which might be more convenient for long-term treatment.[3]

Clinical Studies of Pegzilarginase

Pegzilarginase is being studied in several clinical trials for patients with Arginase 1 Deficiency:

  • PEACE (Pegzilarginase Effect on Arginase 1 Deficiency Clinical Endpoints): A Phase 3 randomized, double-blind, placebo-controlled study evaluating the safety and efficacy of pegzilarginase in children and adults with ARG1-D. This study includes a 24-week double-blind treatment period followed by a long-term extension of up to 150 additional weeks.[3]
  • Long-term safety study: An open-label, multicenter study evaluating the safety of weekly subcutaneous pegzilarginase over 12 months in subjects with ARG1-D.[2]
  • Study for very young patients: A Phase 3 open-label study investigating the safety, pharmacokinetics, and activity of weekly subcutaneous pegzilarginase in subjects younger than 24 months old with ARG1-D.[1]

These studies are designed to evaluate how well the medication works in different age groups and with different methods of administration, as well as to monitor its safety over longer periods of treatment.[1][2][3]

Effectiveness of Pegzilarginase

The primary goal of pegzilarginase treatment is to reduce plasma arginine levels in patients with ARG1-D. The clinical trials measure effectiveness in several ways:

  • Change in plasma arginine concentration from baseline after treatment
  • Proportion of patients achieving arginine levels below 200 μmol/L (the target level set in disease management guidelines)
  • Proportion of patients achieving normal arginine levels (40-115 μmol/L)
  • Changes in other related compounds like ornithine and various guanidino compounds (ARGA, GAA, GVA, NAArg)

These biochemical markers are important because high levels of arginine and its byproducts are toxic to the brain and other organs. Reducing these levels is expected to slow or prevent the progression of neurological damage and other symptoms.[3]

Safety Profile

The clinical trials are carefully monitoring the safety of pegzilarginase. Safety assessments include:

  • Adverse events (AEs): Any undesirable experiences that occur during treatment
  • Hypersensitivity reactions (HSRs): Allergic-type reactions to the medication
  • Injection site reactions (ISRs): Local reactions where the medication is injected
  • Hyperammonemic events: Episodes of high ammonia levels in the blood
  • Safety laboratory tests: Blood tests to monitor organ function
  • Electrocardiograms (ECGs): To monitor heart function
  • Immunogenicity: Development of antibodies against the medication (anti-drug antibodies or ADAs)

These safety monitoring measures help researchers determine if the medication is well-tolerated and identify any potential risks or side effects that patients and healthcare providers should be aware of.[1][2][3]

Mobility and Functional Benefits

Beyond controlling arginine levels, the clinical trials are investigating whether pegzilarginase can improve physical function and quality of life for patients with ARG1-D. Several standardized assessments are being used to measure changes in mobility and function:

  • 2 Minute Walk Test: Measures how far a person can walk in 2 minutes
  • Gross Motor Function Measure (GMFM): Assesses different aspects of gross motor function:
    • GMFM-E: Evaluates walking, running, and jumping abilities
    • GMFM-D: Assesses standing-related tasks
  • Functional Mobility Scale (FMS): Measures the need for assistive devices for walks of different distances (5 meters, 50 meters, and 500 meters)
  • Gillette Functional Assessment Questionnaire (GFAQ): A parent/caregiver assessment of a child’s walking ability
  • Vineland Adaptive Behavior Scales (VABS-II): Measures adaptive behavior in areas like communication, daily living skills, socialization, and motor skills

These assessments help determine whether treatment with pegzilarginase leads to meaningful improvements in patients’ ability to move, perform daily activities, and function independently.[3]

Other Potential Uses of Pegzilarginase

In addition to treating Arginase 1 Deficiency, pegzilarginase is also being investigated for potential use in cancer treatment. A Phase 1/2 study is examining the combination of pegzilarginase with pembrolizumab (a type of immunotherapy) for treating extensive disease small cell lung cancer (ED-SCLC) in patients whose cancer has returned or progressed despite platinum-based chemotherapy.[4]

This cancer application works on a different principle. Some cancer cells are dependent on arginine from the bloodstream for their growth and survival. By depleting arginine with pegzilarginase, researchers hope to starve these cancer cells while also enhancing the effectiveness of immunotherapy.[4]

This potential dual application of pegzilarginase—for both a rare genetic disorder and cancer treatment—highlights the diverse therapeutic potential of this enzyme-based medication.

Study Identifier Target Population Study Design Treatment Duration Administration Method Primary Outcomes
CAEB1102-301A Infants with ARG1-D under 24 months old Open-label, single-arm study 12 weeks with 8-week follow-up Weekly subcutaneous (SC) injection Effect on plasma arginine concentrations
NCT05676853 Patients with ARG1-D (age not specified) Open-label, multicenter study 12 months with 2-week follow-up Weekly subcutaneous (SC) injection Safety assessment (treatment emergent adverse events)
CAEB1102-300A (PEACE) Children and adults with ARG1-D Randomized, double-blind, placebo-controlled study with long-term extension 24-week double-blind period plus 150-week extension Weekly IV infusion with option to switch to SC after 8 weeks of extension Change in plasma arginine concentration; mobility assessments (2-minute walk test, GMFM-E)
CAEB1102-101B Patients with small cell lung cancer Phase 1/2 study of combination therapy Up to 24 months IV administration in combination with pembrolizumab Phase 1: Safety; Phase 2: Objective response rate (ORR)

FAQ

  • What is Pegzilarginase and how does it work? Pegzilarginase (also known as Co-ArgI-PEG, AEB1102, or Loargys) is an enzyme replacement therapy designed to treat Arginase 1 Deficiency. People with this condition lack the enzyme that breaks down arginine, leading to harmful accumulation in the body. Pegzilarginase works by replacing the missing enzyme, helping to reduce plasma arginine levels to more normal ranges, which may improve symptoms of the disease.
  • What conditions is Pegzilarginase being studied for? Pegzilarginase is primarily being studied for Arginase 1 Deficiency (ARG1-D), also known as Hyperargininemia. This is a rare genetic disorder where patients cannot properly break down the amino acid arginine, leading to neurological problems, spasticity, and mobility issues. One clinical trial is also studying pegzilarginase in combination with pembrolizumab for small cell lung cancer, exploring its potential anti-cancer properties.
  • How is Pegzilarginase administered in clinical trials? In the clinical trials, pegzilarginase is administered either through subcutaneous (SC) injection (under the skin) or intravenous (IV) infusion. Most trials involve weekly administration. The treatment periods in these studies range from 12 weeks to 12 months, with some studies including long-term extensions of up to 150 weeks. Some trials start with IV administration and later offer the option to switch to SC administration.
  • What are the main outcomes being measured in the Pegzilarginase trials? The primary outcomes being measured include changes in plasma arginine levels (the main marker of the disease), safety assessments (monitoring adverse events, injection site reactions, and hypersensitivity reactions), and in some trials, improvements in mobility and physical function. Specific mobility tests include the 2-Minute Walk Test and the Gross Motor Function Measure (GMFM). Researchers are also measuring pharmacokinetics (how the drug moves through the body) and pharmacodynamics (how the body responds to the drug).
  • Are there any special considerations for young patients in these trials? Yes, there are specific trials designed for younger patients. One study (CAEB1102-301A) is specifically examining pegzilarginase in children under 24 months of age with Arginase 1 Deficiency. This trial includes special considerations for dosing and monitoring appropriate for this age group. For younger patients, the trials also use age-appropriate physical function assessments like the Gross Motor Function Measure (GMFM) to evaluate treatment effects.

Ongoing Clinical Trials on PEGZILARGINASE

  • Title: Safety and effectiveness study of pegzilarginase weekly injections in children under 2 years old with Arginase 1 Deficiency

    Not recruiting

    1 1 1 1
    Investigated diseases:
    Investigated drugs:
    Austria Portugal

Glossary

  • Arginase 1 Deficiency (ARG1-D): A rare genetic disorder where the body cannot properly break down the amino acid arginine due to the lack of the enzyme arginase 1. This leads to elevated arginine levels in the blood and causes neurological symptoms and mobility problems.
  • Hyperargininemia: Another name for Arginase 1 Deficiency, referring to the abnormally high levels of arginine in the blood that characterize this condition.
  • Pegzilarginase: An investigational enzyme replacement therapy (also known as Co-ArgI-PEG, AEB1102, or Loargys) designed to treat Arginase 1 Deficiency by providing the missing enzyme activity needed to break down arginine.
  • Subcutaneous (SC) administration: A method of giving medication by injecting it under the skin. In the clinical trials, this is one way pegzilarginase is administered to patients.
  • Intravenous (IV) infusion: Administration of medication directly into a vein. Some of the pegzilarginase clinical trials use this method of delivery.
  • Plasma arginine: The amount of the amino acid arginine in the blood plasma. This is the primary measurement used to determine the effectiveness of pegzilarginase treatment.
  • Pharmacokinetics (PK): The study of how a drug moves through the body, including how it's absorbed, distributed, metabolized, and excreted. PK parameters measured in the trials include half-life, maximum concentration, and time to maximum concentration.
  • Pharmacodynamics (PD): The study of how a drug affects the body and how the body responds to the drug. In these trials, this includes measuring changes in plasma arginine and ornithine levels.
  • Adverse events (AEs): Any unfavorable or unintended medical occurrence in a patient during a clinical trial. This includes any symptom, disease, or abnormal laboratory finding, regardless of whether it's related to the study treatment.
  • Hypersensitivity reactions (HSRs): Immune system responses to a drug that can range from mild (like a rash) to severe (like anaphylaxis). These are specifically monitored in the pegzilarginase trials.
  • Injection site reactions (ISRs): Local reactions at the site where a medication is injected, which may include redness, pain, swelling, or itching. These are monitored as part of safety assessments in the trials.
  • Anti-drug antibodies (ADAs): Antibodies that the body produces against a therapeutic drug. These are monitored in the trials to assess the immune response to pegzilarginase.
  • Gross Motor Function Measure (GMFM): A standardized observational instrument designed to measure changes in gross motor function in children. In the trials, GMFM-D assesses standing ability and GMFM-E assesses walking, running, and jumping abilities.
  • 2 Minute Walk Test: A physical performance test that measures the distance a person can walk in 2 minutes. This is used in the trials to assess mobility improvements.
  • Functional Mobility Scale (FMS): A 6-point scale that assesses a person's mobility and need for assistive devices at three different distances: 5 meters, 50 meters, and 500 meters.
  • Individualized Disease Management (IDM): A personalized approach to managing Arginase 1 Deficiency that includes severe protein restriction, essential amino acid supplementation, and ammonia scavengers when indicated. This is used alongside pegzilarginase in the clinical trials.
  • Ornithine: An amino acid produced when arginine is broken down by the arginase enzyme. Measuring ornithine levels helps assess the activity of pegzilarginase.
  • Guanidino compounds: A group of compounds (including ARGA, GAA, GVA, and NAArg) that can accumulate in Arginase 1 Deficiency. Changes in these compounds are measured in some of the trials.
  • RECIST 1.1: Response Evaluation Criteria in Solid Tumors – a standard set of rules used to assess how well cancer patients respond to treatment in clinical trials. This is used in the small cell lung cancer trial with pegzilarginase.

References

  1. https://clinicaltrials.gov/study/NCT06582524
  2. https://clinicaltrials.gov/study/NCT05676853
  3. https://clinicaltrials.gov/study/NCT03921541
  4. https://clinicaltrials.gov/study/NCT03371979