Efgartigimod (ARGX-113) developed by Argenx, is an investigational therapy for autoimmune diseases known to be mediated by immunoglobulin G (IgG) antibodies, including myasthenia gravis (MG). It is designed to lower the number of circulating autoantibodies that wrongly attack healthy tissues.
The therapy has orphan drug status in both the U.S. and Europe. Applications for its possible approval to treat generalized myasthenia gravis are also under review by the U.S. Food and Drug Administration (FDA), the European Medicines Agency (EMA), and regulators in Japan.
How does efgartigimod work?
Antibodies are proteins that the immune system produces in response to foreign molecules invading the body. Also known as immunoglobulins, they fall into five classes: IgG, IgA, IgM, IgD, and IgE. Each class acts slightly differently and responds to different threats. Most antibodies in the blood and fluid that surrounds tissues and cells belong to the IgG class.
In MG, the IgGs that the body produces mistakenly attack portions of the neuromuscular junction (the point at which nerve cells meet muscle cells). Many patients with MG have autoantibodies against the acetylcholine receptor — a protein that binds to the neurotransmitter acetylcholine when it has been released from the nerve cell ending in response to a signal from the brain to relay that information to the muscles. Normally, the binding of acetylcholine to the acetylcholine receptor signals the muscle to contract. However, because the immune system attacks the acetylcholine receptors in MG, acetylcholine cannot bind to them efficiently and the nerve cells cannot send a strong signal to the muscles.
Each antibody has two Fab regions and one Fc region. The Fc region provides the binding site for receptors on the surface of B-cells (the type of immune cell that produces most antibodies), as well as for other antibodies. Efgartigimod is the Fc portion of an antibody that Argenx’ scientists have modified to increase its affinity for IgGs beyond that of normal antibodies. As a result, efgartigimod binds to IgG antibodies, including those that cause MG symptoms.
Efgartigimod is not specific for antibodies that cause MG, however. The medication also will act on antibodies produced by the immune system in response to infections.
Doctors administer efgartigimod as an infusion into the bloodstream.
Efgartigimod in clinical trials
In Phase 1 studies, researchers demonstrated that efgartigimod had favorable safety and tolerability with different doses and dosing regimens. They also showed that the treatment led to promising reductions in the levels of disease-causing IgG.
A Phase 2 study (NCT02965573) to assess the safety, efficacy, and pharmacokinetics (movement in the body) of efgartigimod in MG patients with generalized muscle weakness has been completed. Researchers administered efgartigimod in addition to patients’ current treatment, which included cholinesterase inhibitors, corticosteroids, or immunosuppressants. Results showed that 75% of patients treated with efgartigimod had clinically and statistically significant improvements through at least six weeks, compared to 25% of those on placebo. Researchers reported no severe side effects.
A Phase 3 clinical trial called ADAPT (NCT03669588) evaluated efgartigimod’s safety and effectiveness in 167 adults with MG. The trial enrolled patients both with and without antibodies against acetylcholine receptors (AChR). Participants were randomized to either efgartigimod at 10 mg/kg or to a placebo, in addition to their current standard treatments, for 26 weeks (about six months).
Trial results showed that significantly more AChR-positive patients treated with efgartigimod showed clinically meaningful improvements in the Myasthenia Gravis Activities of Daily Living score, a measure of MG symptom severity, than those on a placebo (67.7% vs. 29.7%), meeting the trial’s main goal. The therapy was also associated with fast, deep, and durable responses among treated patients. Further analyses also showed that efgartigimod was superior to placebo among AChR-negative patients.
Efgartigimod was generally well-tolerated, with a safety profile comparable with that of placebo.
After completing ADAPT, most participants (90%) entered an open-label extension study called ADAPT+ (NCT03770403), in which all enrolled with be treated with efgartigimod for up to three years. Its main goals are to assess the treatment’s safety and tolerability with long-term use, and researchers expect to complete ADAPT+ in mid-2023.
Because efgartigimod interacts with the immune system, it may make patients more susceptible to infections.
An FDA decision on efgartigimod as a treatment for generalized MG is due on or before Dec. 17, 2021, and decisions by regulatory agencies in Europe and Japan are expected in 2022.
Last updated: Aug. 26, 2021
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