Efgartigimod - A Novel Treatment for Myasthenia Gravis

Overview

Myasthenia gravis is an autoimmune neuromuscular disease that causes muscle weakening. Immunoglobulin G antibodies bind to postsynaptic acetylcholine receptors, decreasing neuromuscular transmission. Targeting the neonatal Fc receptor could provide a new therapeutic option for myasthenia gravis. Efgartigimod is a first-in-class neonatal Fc receptor antagonist used to treat autoimmune illnesses such as myasthenia gravis. Intravenous Efgartigimod received its first Food and Drug Administration (FDA) approval in the United States in December 2021 for treating generalized myasthenia gravis in adults with positive anti-acetylcholine receptor (AChR) antibodies. Intravenous Efgartigimod has also been investigated for generalized myasthenia gravis in various countries, with the drug being later authorized in Japan in January 2022 for generalized myasthenia gravis patients irrespective of antibody status and currently in the European Union initial registration stage. It is now undergoing regulatory evaluation as well as clinical development.

Dosage:

• Before beginning a new Efgartigimod therapy cycle, it is critical to deliver age-appropriate immunizations in accordance with immunization standards.

• The recommended dose is 10 mg/kg (milligrams per kilogram), administered once a week for four weeks as a one-hour intravenous infusion. For individuals weighing 120 kg (264.5 pounds) or more, the dosage is 1200 mg (milligrams) per infusion. Clinical evaluation should be used to decide further therapy cycles. The safety of starting subsequent treatments sooner than 50 days after the start date of the previous treatment cycle has yet to be established.

• Before administration, it must be diluted with 0.9 percent sodium chloride injection.

• Give as a one-hour intravenous infusion through a 0.2-micron in-line filter.

Dosage Forms and Strengths:

Efgartigimod is a 400 mg injectable solution in a 20 mL (20 milligrams/milliliter) single-dose vial.

For Patients

What Is Myasthenia Gravis?

Myasthenia gravis is a chronic autoimmune neuromuscular disease characterized by muscle weakness and fatigue. It happens when nerve-muscle transmission fails, resulting in muscular weakening under voluntary control. The condition affects people of all ages, but it is more common in women under the age of 40 and men over the age of 60. Muscle weakness, double vision, drooping eyelids, and trouble speaking, chewing, swallowing, and breathing are all symptoms. The degree of weakness fluctuates, worsening when exhausted and improving after rest.

How Does the Drug Work?

Efgartigimod is a neonatal Fc receptor blocker. Efgartigimod alfa binds to the neonatal Fc receptor (FcRn) and prevents it from recycling immunoglobulin G (IgG) back into circulation. The drug lowers overall IgG levels, including the unusual acetylcholine receptor (AChR) antibodies in myasthenia gravis.

Why Is Efgartigimod Prescribed?

Efgartigimod injections treat myasthenia gravis (a neurological illness that causes muscle weakness). Efgartigimod belongs to a class of drugs known as monoclonal antibodies. It works by decreasing certain natural chemicals in the body that cause myasthenia gravis symptoms.

How Should Efgartigimod Be Used?

Efgartigimod is available as a solution (liquid) that a healthcare provider injects gently into a vein over 60 minutes. It is typically administered once a week for four weeks. The cycle may be repeated as the doctor directs, but at most, 50 days following the last recent weekly dose. The duration of the therapy is determined by how effectively the body responds to the drug and any side effects it experiences.

The injection of Efgartigimod may induce severe allergic responses. The doctor will closely monitor during the Efgartigimod injection and for one hour afterward. The doctor may slow or stop the infusion if patients respond adversely. Inform the doctor immediately if patients have any of the following symptoms:

• Chest discomfort.

• Feeling dizzy.

• Rash.

• Hives.

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

• Hoarseness.

• Difficulty breathing or swallowing.

What Special Precautions Should Be Taken?

The special precautions are:

• If patients are allergic to Efgartigimod, other medications, or any substances in Efgartigimod injection, notify the doctor and pharmacist. Request a list of the components from the pharmacist.

• Inform the doctor and pharmacist about any other prescription and nonprescription drugs, vitamins, nutritional supplements, and herbal products under or intend to use. The doctor may need to adjust the doses of the drugs or closely monitor for side effects.

• Inform the doctor if patients have or have ever had a recurring infection or if patients have or have ever had any other medical issues.

• Inform the doctor if the patient is pregnant, intends to become pregnant, or is nursing. If the patient becomes pregnant while using Efgartigimod, contact the doctor immediately.

• Only get immunizations after consulting the doctor.

Side Effects:

Adverse effects in patients with generalized myasthenia gravis occur in 10 percent, such as

• Respiratory tract infections.

• Headache.

• Urinary tract infections.

Efgartigimod may have unwanted side effects. Inform the doctor if any of the following symptoms are severe or persistent:

• Muscle soreness.

• Burning.

• Numbness or tingling sensations in the extremities or mouth.

Some of the side effects can be severe. If patients suffer any of the following symptoms, contact the doctor right away:

• Fever, sore throat, chills, cough, or other infection-related symptoms.

• Pain or burning urination or frequent urination.

Other adverse effects of Efgartigimod are possible. If patients have any abnormal side effects while taking this medicine, contact the doctor immediately.

Storage:

Refrigerate Efgartigimod vials in their sealed carton at 2°C to 8°C (36°F to 46°F) to protect them from sunlight until use. Do not freeze or shake.

What Can Be Done in the Event of an Overdose?

There are no specific signs and symptoms of Efgartigimod overdose. Call emergency services or the poison control center immediately in case of an overdose. The adverse effects experienced at the indicated dose are not likely to alter in the event of an overdose. There is no specific antidote for Efgartigimod overdose.

For Doctors:

Indications:

Efgartigimod treats anti-acetylcholine receptor (AChR) antibody-positive adult patients with generalized myasthenia gravis.

What Are the Pharmacological Aspects of Efgartigimod?

Pharmacodynamics:

Efgartigimod acts pharmacologically by lowering the circulating autoantibody that causes myasthenia gravis symptoms. It is given as a once-weekly intravenous infusion for four weeks per treatment session, with the possibility to begin additional treatment cycles if clinically suggested once at least 50 days have passed since the previous cycle. As Efgartigimod lowers circulating IgG levels, patients taking treatment may be more susceptible to infection due to a suppressed immunological response. It should not be started in patients with an active infection and should be considered in patients who develop a significant infection during a treatment cycle.

Mechanism of Action:

Myasthenia gravis (MG) is an autoimmune illness that affects the skeletal muscles' neuromuscular junction. Developing IgG autoantibodies to endogenous proteins such as acetylcholine receptors (AChRs) is one of its pathophysiologic processes. These proteins are degraded by the Membrane Attack Complex (MAC), which limits electrical impulse transmission and causes muscle weakness. In the vascular endothelium, immunoglobulin G passes through a recycling phase, which may disrupt neuromuscular transmission. Efgartigimod alfa, a human IgG1 antibody fragment, binds to FcRn, blocking IgG recycling and lowering circulating IgG levels, including autoantibodies that cause myasthenia gravis.

Half-Life in Adults: The average half-life of Efgartigimod in adults is 80 to 120 hours.

Pharmacokinetics:

• Absorption: Efgartigimod exhibits linear pharmacokinetics, with exposures increasing proportionally up to 50 mg/kg (five times the therapeutic dosage) after a single administration.

• Distribution: The distribution volume ranges from 15 to 20 liters.

• Metabolism: Efgartigimod is expected to be broken down into small peptides and amino acids by proteolytic enzymes.

• Excretion: In healthy subjects, less than 0.1 percent of the administered dose was retrieved in the urine, followed by a single intravenous dose of 10 mg/kg Efgartigimod.

Clinical Trials

1. A 26-week multicenter, randomized, double-blind, placebo-controlled trial was done to investigate the efficacy of Efgartigimod in people with AChR antibody positivity for treating generalized myasthenia gravis. The study included 167 patients who met specified screening criteria, such as

• Clinical classification of Myasthenia Gravis Foundation of America (MGFA) class II to IV. Myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL) total score of five.

• A stable dose of MG treatment before screening.

• IgG levels of at least six g/L.

• Positive AChR antibodies.

The effectiveness of Efgartigimod was assessed using the Myasthenia Gravis-Specific Activities of Daily Living scale (MG-ADL), which analyzes the impact of generalized myasthenia gravis on eight signs and symptoms of myasthenia gravis. A statistically significant difference favoring Efgartigimod in the MG-ADL responder rate was found during the first treatment cycle. The total score for Quantitative Myasthenia Gravis (QMG) was also assessed, and there was a statistically significant difference in the QMG responder rate favoring Efgartigimod during the first therapeutic session.

2. Efgartigimod was demonstrated to dramatically enhance muscle strength and reduce the requirement for rescue therapy in patients with generalized myasthenia gravis in a Phase 3 clinical trial called ADAPT. The trial included over 100 patients and revealed that Efgartigimod was well tolerated, with most side effects being mild to moderate in severity. These encouraging findings have opened the path for Efgartigimod to be approved by regulatory authorities in a number of countries.

Warnings and Precautions:

The warnings and precautions associated with Efgartigimod are as follows:

• Infections: Efgartigimod can raise the risk of infection; the most common infections are urinary tract and respiratory tract infections. Efgartigimod lowers white blood cell, lymphocyte, and neutrophil counts. Many infections and hematologic abnormalities were mild to moderate. Patients with current infections should avoid Efgartigimod until the infection has subsided. Because Efgartigimod reduces IgG levels, live-attenuated or live vaccinations are not indicated.

• Infusion Reactions: Infusion reactions, such as redness or pruritus, are possible. These were mild to moderate in the clinical trial and did not result in treatment suspension or cessation. Patients should be watched for clinical signs and symptoms of infusion responses throughout the administration and one hour afterward. If a reaction occurs, the infusion should be stopped and appropriate supportive measures implemented. Once resolved, administration can be continued at a slower pace if necessary.

• Hypersensitivity: Efgartigimod-treated patients have experienced hypersensitivity events such as rash, angioedema (a type of non-pitting edema that affects the subcutaneous and/or submucosal layers of the face, lips, neck, extremities, oral cavity, larynx, and/or gut), and dyspnea (the sense of running out of air and being unable to breathe quickly or deeply enough). These mild to moderate responses occur within one to three weeks of medication and do not require therapy cessation. Patients should be observed during administration and for one hour afterward, and if an event takes place, the infusion should be stopped and supportive measures implemented.

Drug Interactions:

Concurrent use of Efgartigimod with medications that bind to the human neonatal Fc receptor (FcRn), such as immunoglobulin products, monoclonal antibodies, or Human Fc domain antibody derivates from the IgG subclass, may lower systemic exposures and drug efficacy. Medication that binds to the human neonatal Fc receptor should be closely monitored for decreased efficacy. Consider quitting Efgartigimod and utilizing alternate therapy if concomitant long-term usage of such medicines is essential for patient care.

Use in specific populations:

• Pregnancy: In rats and rabbits, Efgartigimod, a monoclonal antibody, has no known adverse developmental effects. The amount of significant birth defects and miscarriages is unclear. It could be passed from mother to fetus, lowering maternal IgG antibody levels. The treatment of Efgartigimod (0, 30, or 100 mg/kg/day) intravenously to pregnant rats and rabbits during organogenesis, gestation, and lactation had no negative effects on prenatal or postnatal development.

• Lactation: Efgartigimod's presence in human milk is unknown. Human milk contains maternal IgG as well. The advantages of breastfeeding should be weighed against the mother's clinical requirement for Efgartigimod and any potential negative effects.

• Pediatric Use: There is no evidence of safety or efficacy in pediatric patients.

• Geriatric Use: Efgartigimod clinical trials did not involve a large enough number of patients aged 65 and older to assess whether the patient responded differently than younger adult patients.

• Impaired Renal Function: No dose change of Efgartigimod is required for patients with modest renal impairment. There is insufficient evidence to determine the influence of mild renal impairment (eGFR 30-59 mL/min/1.73 m2) and severe renal impairment (eGFR 30 mL/min/1.73 m2) on the pharmacokinetic properties of Efgartigimod.