FcRn Blocker Offers Hope to gMG Patients ‘Left Out in Cold’

The first-in-class neonatal Fc receptor (FcRn) antagonist efgartigimod significantly improved daily functioning in patients with generalized myasthenia gravis who lack detectable anti-acetylcholine receptor (AChR) antibodies, with benefits increasing over repeated treatment cycles, results from a phase 3 trial showed.The investigators found “that efgartigimod is efficacious in all forms of myasthenia gravis, regardless of their antibody status,” study investigator James F. Howard Jr, MD, professor of neurology, medicine and allied health, and director of the Myasthenia Gravis Clinical Trials and Translational Research Unit, University of North Carolina at Chapel Hill, told Medscape Medical News.The findings were presented on September 29 at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2026.Generalized myasthenia gravis (gMG) is a rare, chronic autoimmune neuromuscular disease that leads to a loss of muscle function and severe weakness.Some patients with gMG have no detectable anti-AChR antibodies. These include individuals who test positive for antibodies against muscle-specific kinase or low-density lipoprotein receptor-related protein 4, as well as those with triple-seronegative gMG, who lack detectable antibodies against all three targets.Such patients are often misdiagnosed. Without specific antibodies, gMG is difficult to detect, as symptoms can mimic other conditions such as muscular dystrophies, said Howard.They have historically been excluded from clinical trials, leading to a significant unmet need, he said. “These patients with no antibodies get left out in the cold.”Efgartigimod targets the FcRn, reducing circulating immunoglobulin G levels, including disease-causing autoantibodies. It is being investigated in patients with gMG who lack detectable anti-AChR antibodies.“It has become recognized as a very efficient way to clear antibodies from the body,” said Howard.Earlier studies suggested that efgartigimod may benefit patients with gMG or ocular MG. A separate trial demonstrated that subcutaneous administration was noninferior to intravenous (IV) administration.The current phase 3 trial, ADAPT SERON, enrolled 119 adults with gMG who lacked detectable anti-AChR antibodies, had a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 5, and were receiving stable treatment. Participants had a mean age of approximately 51 years; 76% were female, and most were White.In part A, participants were randomly assigned to receive once-weekly IV efgartigimod (10 mg/kg) or a placebo for 4 weeks. Mean baseline MG-ADL total scores were 9.9 in the efgartigimod group and 9.4 in the placebo group.Triple-seronegative status was the most common antibody profile, accounting for 55.2% of the efgartigimod group and 67.2% of the placebo group. Approximately two thirds of participants were taking a corticosteroid. The primary endpoint was the MG-ADL total score at week 4.Efgartigimod significantly improved MG-ADL total scores at week 4 compared with placebo. The least squares (LS) mean change from baseline was -3.35 with efgartigimod vs -1.90 with placebo (LS mean difference, -1.46; 95% CI, -2.33 to -0.58; P = .007).Participants who completed part A could enter the ongoing open-label part B, receiving IV efgartigimod in cycles of 4 weeks on treatment followed by 4 weeks off. At the time of the presentation, 60% completed cycle 9.Responses deepened with repeated treatment, Howard reported.“We saw that the improvement actually got even better, so that the depth of response was better than what we saw in Part A alone.”Sustained ImprovementImprovements in MG-ADL total scores were sustained through week 52 in the overall study population, Howard said. The cumulative proportion of participants who achieved minimal symptom expression (MSE), defined as an MG-ADL score of 0 or 1, increased over nine treatment cycles.Participants in all three antibody subgroups achieved MSE during treatment. “What stood out is that individuals, regardless of whether they have antibodies or not, regardless of the type of antibodies they have, they will respond,” Howard said. Some participants who did not respond to the first treatment cycle responded to the second or third, Howard noted. “So one should not abandon the therapy; there’s still the potential to get better.”He recommended at least 3-4 treatment cycles “before we consider it not efficacious and look for something else.”Treatment was well tolerated. At the time of analysis, 87.3% of participants had experienced at least one treatment-emergent adverse event (TEAE), and 23.7% had experienced at least one serious TEAE. The most common TEAEs were upper respiratory tract infections, headache, and urinary tract infections.The study was funded by argenx. Howard’s institution reported receiving funding from argenx and other pharmaceutical companies and groups. Howard reported receiving honoraria/consulting fees, as well as nonfinancial support, from argenx and other groups.