Avalglucosidase Alfa-Ngpt - Safety and Efficacy in the Battle Against Late-Onset Pompe Disease

Overview

Avalglucosidase alfa-ngpt is a medication of enzyme replacement therapy in the treatment of glycogen storage disease type II or Pompe disease. Enzyme replacement therapy is known for replacing or restoring the enzyme that is absent or deficient in the system. So, here, the deficient enzyme lysosomal acid alpha-glucosidase is thus restored.

Avalglucosidase alfa-ngpt is used significantly in the intervention of late-onset Pompe disease and Pompe disease generally. This enzyme therapy has become a new and essential treatment aid for the late-onset form of Pompe disease. Avalglucosidase alfa-ngpt got its approval for medical use in August 2021 in the United States and June 2022 in the European Union. The Food and Drug Administration (FDA) approved Avalglucosidase alfa-ngpt, an important treatment, on August 6, 2021.

How Does Avalglucosidase Alfa-Ngpt Work?

Avalglucosidase alfa-ngpt is a therapy for enzyme replacement in those with deficient levels of the lysosomal acid alpha-glucosidase enzyme. It is designed to target and bind the mannose-6-phosphate receptor, which forms the vital pathway for transporting the enzyme into the lysosomes in the cells. So, it improves cellular uptake. This, in turn, enunciates the breakdown or cleavage mechanism of complex sugars known as glycogen. As a result, glycogen clearance is enhanced.

Prescriptions

Avalglucosidase alfa-ngpt is a medication available in injections that doctors and other healthcare professionals inject and infuse in hospital settings. Enzyme therapy is generally prescribed for Pompe disease. Pompe disease is an inherited glycogen storage disorder characterized by excess glycogen buildup in the muscle cells due to the deficiency of the enzyme. With progression, Pompe disease results in impairment of the ability to breathe and move. So, it causes an intense degree of muscle weakness, immobilization, and respiratory concerns.

Drug and Its Dosages

Route of Administration: Intravenous injection.

Drug Form and Strength:

• 100 mg/vial.

• Lyophilized powder for reconstitution.

Drug Dosages:

• Indicated in the late-onset Pompe disease.

• The dose is dependent on the actual body weight and certain medical factors.

• If an individual weighs greater than 30 kg, the recommended dosage is 20 mg/kg IV once every two weeks.

What Are the Precautions and Warnings for Avalglucosidase Alfa-Ngpt?

• Allergy: Avalglucosidase alfa-ngpt can cause hypersensitivity reactions in people who are generally allergic to it. In addition, it can precipitate severe yet potentially life-threatening allergic reactions referred to as anaphylaxis. The alarming signs include rashes, hives, tongue, face, or lips swelling, and trouble breathing. One should rightly seek emergency care in these cases. Moreover, one should not retake the medication with a known history of allergy since it would lead to fatal.

• Pregnancy: No appropriate data from studies determine the drug-associated risk in pregnant women and fetuses. The doctors will consider certain determinants and advise which is safe for the individual. So, the drug should be taken at the time of pregnancy only if required. So, one should inform the doctor about the pregnancy or any plan for pregnancy. Also, untreated Pompe disease can lead to severe degrees of complications in individuals, so the condition is to be treated.

• Breastfeeding: The clinical data validating the use of Avalglucosidase alfa and its risk during breastfeeding are inadequate. However, one must be cautious and inform the healthcare professionals in the case of breastfeeding so that the doctors consider the potential benefits and risks before prescribing.

• Children: Avalglucosidase alfa is not recommended and advised for infants under one year of age since safety and efficacy have not been established. The indication of the drug is limited to individuals one year of age and older.

• Geriatrics: So far, clinical studies have not demonstrated the efficacy and geriatric-specific concerns that restrict the use of Avalglucosiade alfa-ngpt enzyme therapy in elderly adults.

Significant Warnings

Avalglucosidase alfa-ngpt has significant or black box warnings for the following effects.

• Hypersensitivity reactions.

• Infusion-related reactions.

• Cardiorespiratory failure.

For Patients

What Is Pompe Disease?

Pompe disease, also known as glycogen storage disease II or acid-maltase disease, is a rare form of the inherited disorder where the complex sugar called glycogen accumulates and builds up in the body cells. Pompe disease occurs as a result of the deficiency of the enzyme acid alfa glucosidase (GAA), whereas the enzyme is responsible for breaking down the complex sugars in the system. As a consequence, the buildup occurs in tissues and muscles, resulting in breakage. So, the disease might cause progressive degrees of weakness in the skeletal and cardiac muscles.

What Are the Symptoms of Late-Onset Pompe Disease?

Pompe disease may occur in the initial few months from birth, referred to as classic infantile-onset Pompe disease, or at times occurring within the first year of age in a non-classic form of infantile-onset Pompe disease. In contrast, signs can be encountered in later life, including childhood or adulthood; this incidence is known as late-onset Pompe disease. This type is also referred to as juvenile or adult late onset-pompe disease. The predominant signs of late-onset Pompe disease include muscle weakness, particularly in the legs and torso. The other characteristic features of the condition include the following:

• Swaying gait.

• Difficulty standing after other tasks.

• Facial, spine, breathing, and swallowing muscles are affected as the muscle weakness worsens.

• Scoliosis.

• Muscle aches and spasms.

• Fatigue.

• Headache.

• Respiratory problems as a result of muscle weakness in the aspects of the intercoastal and diaphragm.

How Does Avalglucosidase Help Treat the Late Onset of Pompe Disease?

Pompe disease is a form of glycogen storage disease where the individual has an excessive accumulation or buildup of a complex sugar called glycogen in the cells, particularly in the muscle cells. This is due to the genetic defect in the GAA gene, which results in a reduced concentration of acid-alpha glucosidase enzyme. This enzyme is responsible for the breakdown of glycogen into glucose. And so the glycogen gets buildup. Avalglucosidase alfa-ngpt is an enzyme replacement intervention, and here, the enzyme Avalglucosidase alfa is restored in deficient individuals. As a result, it enhances the breakdown or cleavage process of glycogen.

How to Get Avalglucosidase Therapy?

• Doctors and other medical healthcare professionals administer the Avalglucosidase alfa-ngpt injection into the vein in hospitals or medical settings.

• The injection is administered gradually so the individual stays in place for about four hours.

• The Avalglucosidase alfa-ngpt injection is generally prescribed once every two weeks. However, the doctors might modify the length and dosing of the therapy, considering the individual’s response and reactions toward the drug.

• The dosage is generally based on the medical condition, the severity of the Pompe disease, the individual’s weight, and the response to intervention.

• A few medications in the form of tablets or infusions are advised before Avalglucosidase alfa-ngpt injection in order to reduce the risk of infusion-related adverse reactions.

• One should follow the doctor’s directions conscientiously.

• Also, one should not stop the Avalglucosidase alfa-ngpt therapy without the doctor’s consent.

What Are the Things to Consider and Inform the Doctor Before Commencement?

• One should inform the doctor if one is allergic to Avalglucosidase alfa-ngpt. Also, inform the doctor if one is allergic to other ingredients in the prescribed medication.

• With all, tell the doctor if the person is taking or about to take any medications, vitamins, nutritional intake, or herbal supplements. Hence, the doctors would adjust the dosage or asses attentively for any adverse reaction.

• Subsequently, inform the doctor about the present and past medical diseases, illnesses, and conditions.

• Convey to the doctor if one is pregnant, breastfeeding, or has any plans for pregnancy.

• Call and inform the doctor if one gets pregnant during Avalglucosidase alfa-ngpt treatment.

Dietetic Consideration

One can follow the routine classical diet and way of eating until the doctor utters any limitations or restrictions. Nevertheless, a well-balanced, nutritious, and healthy diet is always meant for good physical, emotional, and social health.

Disclamation

Avalglucosidase alfa can make one dizzy. Also, the drug indulges in causing increased degrees of dizziness when it is used with alcohol or marijuana. In such cases, one should not drive, hold machinery, or do other strenuous activities requiring high alertness. So, one should limit alcohol. Also, convey to the doctor if one is using or addicted to alcohol or marijuana.

What if One Misses the Dose of Avalglucosidase Alfa-Ngpt?

It is essential to get the doses correctly at the appropriate schedules. Reach out to the doctor and ask for the new dosing schedule if one misses the dose or appointment. The doctors will advise on either withholding or rescheduling.

In Cases of Overdosage

Overdose does not usually result from Avalglucosidase alfa injection as the administration is given in hospital settings. Nevertheless, reach out to the emergency helplines or healthcare professionals in case of overdosage or emergency concerns, including difficulty breathing or collapse.

How Effective Is Avalglucosidase Alfa-Ngpt?

Avalglucosidase alfa-ngpt was approved to be the new standard intervention in late-onset Pompe disease because of its long-term efficacy and safety profile. The clinical findings show that the drug presented good tolerance with no incidence of death. Hence, Avalglucosidase alfa proved to be an effective enzyme therapy, thus serving as a new significant treatment option.

Side Effects

Avalglucosidase alfa-ngpt is a safe and effective medicine. However, It presents certain side effects but is mild and usually resolves on its own in time. If they worsen or do not resolve, one must talk with the health care professionals.

• Dizziness.

• Headache.

• Nausea.

• Vomiting.

• Diarrhea.

• Tiredness.

• Rash.

• Itching.

• Redness.

• Difficulty breathing.

• Muscle and joint pain.

• Tingling or numbness.

• Burning sensation.

Serious Side Effects

Serious negative reactions can occur with Avalglucosidase in the form of hypersensitivity reactions or infusion-related reactions. In such cases, one should get in contact with a doctor right away. Seek medical emergencies immediately if the symptoms seem to be potentially life-threatening.

The following are the possible severe degrees of side effects of Avalglucosidase alfa.

• Difficulty breathing.

• Hives.

• Rash.

• Swelling of face, tongue, lips, or throat.

• Severe degrees of dizziness.

• Chest discomfort.

• Redness or tingling sensation.

• Itching.

• Cough.

• Wheezing.

• Pale skin.

• Bluish lips or fingernails.

• Difficulty swallowing.

• Swelling of tongue.

• Nausea.

• Flushing.

For Doctors

Pharmacological Data

Generic Name: Avalglucosidase alfa-ngpt

Drug Class: Enzyme

Chemical Formula: C4490H6818N1197O1299S32

Molar Mass: 99 376.93 G.MOL-1

Indications

Avalglucosidase alfa-ngpt is a hydrolytic lysosomal form of the glycogen-specific enzyme indicated in the treatment of individuals with late-onset Pompe disease, whereas Pompe disease results from lysosomal acid alpha-glucosidase deficiency.

Associated Conditions

• Late-onset Pompe disease.

• Pompe’s disease.

Associated Intervention

• Enzyme replacement therapy in Pompe Disease.

Pharmacology of Avalglucosidase Alfa-Ngpt

Mechanism of Action

• Pompe disease, also referred to as glycogen storage disease type II or acid maltase deficiency, is a genetic type of glycogen metabolism disorder.

• It occurs as a result of mutations in the recombinant alpha-glucosidase (GAA) gene, which encrypts an enzyme called lysosomal hydrolase acid alpha-glucosidase.

• This enzyme is generally responsible for the catalyzation of hydrolysis of glycogen so as to release glucose for absorption and cellular functions.

• So, deficiency of GAA results in intralysosomal glycogen accumulation in tissues and progressive cellular disruption, particularly in cardiac, smooth, and skeletal muscles.

• Avalglucosidase alfa-ngpt is an enzyme replacement therapy that replaces and restores the GAA enzyme in the system.

• Avalglucosidase alfa-ngpt is a hydrolytic lysosomal form of the glycogen-specific recombinant human enzyme, which plays an essential role in normal muscle function and development.

• It exists in conjugation with multiple and synthetic bis-mannose six phosphate tetra-mannose glycans.

• It works by binding of mannose-6-phosphate of aval glucosidase alfa to the cation-independent form of mannose-6 phosphate receptor on the cell surface, enhancing high affinity.

• It is then internalized and transmitted to lysosomes for undergoing proteolytic cleavage. Now, GAA enzyme activity is increased eventually.

• Avalglucosidase alfa then wields enzyme activity for the cleavage of glycogen.

Pharmacodynamics

According to the clinical trials and study findings, patients with Pompe disease showed reduced glycogen levels after Avalglucosidase alfa therapy. These results indicate that the Avalglucosidase alfa enzyme therapy efficiently cleaved the excess glycogen in the system. The studies also show that aval glucosidase alfa depicts higher affinity over the cation-independent form of mannose-6 phosphate receptor in both ways as effective muscle targeting and cellular uptake.

Absorption

• The increase in exposure to Avalglucosidase is apparent with an approximate proportional means with an increase of dosages.

• With intravenous infusion, the peak plasma concentration of Avalglucosidase at week one is 259 mcg/mL, and at week two is 242 mcg/mL.

• The mean range of plasma AUC is approximately 1290 mcg/mL at week one and 1250 mcg/mL at week 49.

Distribution

• The volume of distribution for Avalglucosidase alfa-ngpt is 3.4 L in people with late onset of Pompe disease.

• No evidence of accumulation is seen on a weekly basis of two-week dosing schedules.

Metabolism

• The extensive metabolic pathway of Avalglucosidase alfa is not characterized.

• Nevertheless, the protein aspect of the drug is predicted to undergo metabolism into end products, such as small peptides and amino acids, by means of catabolic pathways.

Elimination

• The clinical findings validating the route of elimination are limited.

• The mean half-life of Avalglucosidase alfa-ngpt in individuals with late-onset Pompe disease is 1.6 hours.

Clearance

• The mean clearance is about 0.9 L/hour in the late onset of Pompe disease.

Adverse Effects

The following are the significant adverse reactions of Avalglucosidase.

• Hypersensitivity reactions, including anaphylaxis.

• Infusions-related reactions.

• Headache.

• Diarrhea.

• Nausea.

• Fatigue.

The other less common or race incidences of adverse effects include the following:

• Dizziness.

• Arthralgia.

• Myalgia.

• Vomiting.

• Pruritus.

• Erythema.

• Dyspnea.

• Paresthesia.

• Urticaria.

• Anaphylaxis.

• Severe degrees of hypersensitivity reactions.

Dosing Considerations:

Avalglucosidase alfa-ngpt is solely indicated in the treatment of late-onset Pompe disease in individuals one year of age and older. The following considerations are to be taken into account for Avalglucosidase therapy.

• Suggest pretreatment of antihistamines, corticosteroids, and antipyretics prior to Avalglucosidase administration.

• It is recommended to employ an in-line, 0.2-millimeter filter with low-protein binding for the administration of Avalglucosidase.

• Avalglucosidate alfa is to be reconstituted and diluted before use.

• Incremental infusion is generally recommended, subject to the individual’s response.

• The drug is administered with intravenous injection. So, the recommended dosage is 20 mg/kg every two weeks for greater than 30 kg. The recommended dosage is 40 mg/kg every two weeks for less than 30 kg.

• The recommended infusion rate is initially one mg/kg/hour.

• The infusion rate is to be gradually raised every thirty minutes in cases of individuals presenting no signs of infusion-related reactions.

Dosing Modifications:

The following dosing modifications are to be applied in certain degrees of hypersensitivity reactions, in particular, anaphylaxis and infusion-associated reactions (IAR).

1. In cases of severe hypersensitivity reactions (inclusive of anaphylactic reaction) or severe infusion-related reactions, discontinue the Avalglucosidase alfa therapy promptly and initiate the appropriate medical intervention.

2. In cases of mild to moderate degrees of hypersensitivity reactions and moderate infusion-related reactions, take into consideration either holding the infusion temporarily or diminution the infusion rate. Also, initiate appropriate medical intervention. Eventually, the following means are to be considered according to their symptoms.

• If the symptoms persist even with transiently holding of infusion, wait at a minimum of thirty minutes for those symptoms to settle before an intent of stopping the therapy.

• If the symptoms subside, consider recommencing the infusion for about thirty minutes at half the rate at which the individual presented reactions. Increase the infusion rate by about fifty percent for fifteen to thirty minutes. In cases of no recurrence of symptoms, increase the infusion rate gradually in an incremental manner.

Clinical Trials

A clinical-trial-based study demonstrated the safety and efficacy profile of Avalglucosidase by comparing it with Aglucosidase. The trial was randomized, three-phased, and multicentral. The study validated and provided evidence of significant clinical improvement in respiratory function, functional endurance, and ambulation with Avalglucosidase over the drug Aglucosidase.

Another Pivotal phase three trial-based study validated the efficacy of Avalglucosidase in the late-onset Pompe disease. The clinical findings showed overall improvements in walking distance and respiratory function concerning skeletal and respiratory muscles, respectively.