Phase 3 Trial to Assess Therapeutic Effect of IV Efgartigimod in Seronegative Myasthenia Gravis

Author(s):

Key Takeaways

ADAPT SERON assesses efgartigimod's efficacy in seronegative gMG patients, a group often excluded from traditional trials.
Efgartigimod, approved for seropositive gMG, binds to the neonatal Fc receptor and has expanded indications.
The study involves 110 patients, using MG-ADL score changes as the primary endpoint, with a double-blind and open-label extension.
Participants must have acquired gMG with specific diagnostic criteria and are excluded if they have interfering autoimmune diseases or recent thymectomy.

The phase 3 study is expected to include 110 patients with seronegative myasthenia gravis who will be randomly assigned to IV efgartigimod or placebo for a 5-week follow-up, followed by an open-label extension.

Jeffrey Guptill, MD, MS

A new study, dubbed ADAPT SERON (NCT06298552) will assess the efficacy and safety of intravenous (IV) efgartigimod (Vyvgart; Argenx), an FDA-approved therapy, in patients with generalized myasthenia gravis (gMG) who are anti-acetylcholine receptor antibody negative (AChR-Ab-). This trial is significant considering patients with seronegative gMG are often led out of traditional gMG trials that test investigational agents.¹

Efgartigimod, a drug that treats autoimmune diseases by binding to the neonatal Fc receptor (FcRn), was first approved in 2021 in an IV form as a treatment for seropositive gMG.² Since then, the FDA has expanded its indication to include patients with chronic demyelinating neuropathy, as well as approved a new subcutaneous version of the therapy for easier administration.

The new study, presented at the 2024 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting, held October 15-18, in Savannah, Georgia, has an expected enrollment of 110 patients who will be randomly assigned to 10 mg/kg efgartigimod IV or placebo. ADAPT SERON will use change in Myasthenia Gravis-Activities of Daily Living (MG-ADL), a traditionally used measure, as the primary end point. The trial is comprised of 2 stages: a double-blinded, placebo-controlled Part A, consisting of 4 once-weekly infusions and 5 weeks of follow-up, and the open-label extension Part B, consisting of varying number and frequency of cycles and weekly infusions for up to 2 years.

Led by Jeffrey Guptill, MD, MS, an associate professor of neurology at Duke University, the study also includes secondary outcomes, such as change in Quantitative Myasthenia Gravis (QMG) total score and proportion of participants who are both MG-ADL and QMG responders. According to clinicaltrials.gov, the trial is expected to initially conclude in mid-2025, with the final open-label extension lasting until 2027.

To be included in the study, participants must have a diagnosis of acquired gMG of both of the following: (1) history of abnormal neuromuscular transmission demonstrated by single fiber electromyography or repetitive nerve stimulation (RNS) or is anti-muscle-specific kinase antibodies (MuSK-Ab) seropositive; (2) either a history of positive edrophonium chloride test OR a demonstrated improvement in MG signs with treatments such as oral AChE inhibitors, plasma exchange, immunoabsorption, or intravenous immunoglobulin/ subcutaneous immunoglobulin treatment.

The study excludes those with an any known autoimmune disease or condition that would interfere with an accurate assessment of clinical symptoms of gMG. In addition, those with clinically significant active infection, known hypersensitivity to the study drug, and have received a thymectomy less then 3 months before screening, are also excluded. In addition, the study also bars those with have gotten a live or live-attenuated vaccine in the 4 weeks before screening.

In most cases of MG, autoantibodies can be detected in the sera, thus aiding in diagnosis and allowing for early screening; however, there is a small proportion of patients who have no detectable auto-antibodies, known as “seronegative MG.” Several factors contribute to this, including laboratory test inaccuracies, decreased antibody production, immunosurppressive therapy, immunodeficiencies, antigen depletion, and immune-senescence. While radioimmunoassasys have been considered the standard method for detecting MG antibodies, improved and highly sensitive cellular assays or radioimmunoprecipiation assays have made it positive to detect anti-AChR and anti-MuSK antibodies in patients previously diagnosed with seronegative MG.³

The approval for the IV formulation of Efgartigimod was based on the phase 3 ADAPT trial (NCT03669588). ADAPT featured 167 patients with gMG, of which 77% (n = 129) were AChR-Ab+. Findings of the study showed that efgartigimod was well-tolerated and efficacious in treating patients with gMG, with the drug meeting the primary end point by improving MG-ADL scores for patients with AChR-Ab+ gMG compared with those in the placebo group (67.7% vs. 29.7%; P <.0001). Additionally, 40.0% of efgartigimod-treated AChR-Ab+ patients achieved minimal or no symptoms compared with 11.1% treated with placebo.⁴

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REFERENCES
1. Guptill J, Jimenez RH, Howard JF. Phase 3 trial investigating impact of intravenous efgartigimod in anti-acetylcholine receptor antibody negative generalized myasthenia gravis. Presented at: 2024 AANEM Annual Meeting; October 15-18; Savannah, GA. ABSTRACT 178
2. FDA Approves New Treatment for Myasthenia Gravis. News release. FDA. December 17, 2021. Accessed October 17, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-myasthenia-gravis
3. Vinciguerra C, Bevilacqua L, Lupica A, et al. Diagnosis and management of seronegative myasthenia gravis: lights and shadows. Brain Sci. 2023;13(9):1286. doi:10.3390/brainsci13091286
4. Howard JF, Bril V, Vu T, et al. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2021;20(7):526-536. doi:10.1016/S1474-4422(21)00159-9