SAN FRANCISCO — Efgartigimod (Vyvgart), a neonatal Fc receptor (FcRn) antagonist, significantly improved symptoms in patients with anti-acetylcholine receptor antibody (AChR-Ab)-negative generalized myasthenia gravis (gMG), a group that has traditionally lacked effective treatment options.

In the phase 3, randomized, double-blind, placebo-controlled ADAPT SERON trial, patients receiving efgartigimod achieved a statistically significant least squares mean change from baseline in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score at 4 weeks compared with placebo (-3.35 vs -1.90; P = .007), reported James F. Howard, Jr, MD, of the University of North Carolina, Chapel Hill.

The findings were presented October 29 at the American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) 2025.

A Neglected Population

Patients with AChR-Ab-negative gMG account for about 15%-20% of the overall patient population with gMG. The group includes patients with antibodies to MuSK protein (roughly 5%-10%); those with antibodies to LRP4 (roughly 1%-5%); and triple-seronegative patients (roughly 10%), who have no detectable autoantibodies against acetylcholine receptor, MuSK, or LRP4.

“The seronegative patient is a very difficult population for clinicians to treat…and it’s a population that we have neglected for decades in all of our clinical trials. This is an attempt to remedy that,” Howard said. 

AChR-Ab-negative gMG can be difficult to diagnose. Investigators noted that there are many possible explanations for negative antibody tests, including autoantibody levels below detection limits, autoantibodies against unrecognized epitopes not detected by assay, and autoantibodies against unknown targets.

The ADAPT SERON study enrolled adult patients with AChR-Ab-negative gMG, Myasthenia Gravis Foundation of America class II-IV disease, and an MG-ADL score of at least 5. All were on stable baseline therapy.

The trial had two parts. In part A, an 8-week randomized, placebo-controlled phase, patients were randomly allocated in a 1:1 ratio to receive four intravenous doses of efgartigimod 10 mg/kg at weekly intervals or placebo. This was followed by a 5-week observation period.

Efgartigimod was approved by the FDA 2021 for AChR-positive gMG.

Part B, which is ongoing, is an open-label extension with two initial treatment cycles of the same dose as in part A for all participants: 4 weeks on, 4 weeks off. This is followed by four once-weekly doses followed by individualized time between cycles based on clinical response.

At baseline, the 58 participants in the efgartigimod group had a mean age of 50.6 years and 75.9% were female; 82.8% were White, 13.8% Asian, 1.7% Black/African American, and 1.7% other race/ethnicity.

The 61 participants in the placebo group had a mean age of 51.7 years (SD, 13.0) and 75.4% were female; 76.7% were White, 13.3% Asian, 3.3% Black/African American, and 6.7% other race/ethnicity. 

The mean MG-ADL scores in the groups were 9.9 and 9.4, respectively. Among 40 MuSK-Ab seropositive participants, efgartigimod showed a least squares mean change of -4.24 vs. -1.89 with placebo (treatment difference, -2.35; P = .01), demonstrating a statistically significant improvement favoring efgartigimod.

One Suspected Drug-Related Death 

In the triple-seronegative subgroup (n = 73), efgartigimod showed a least squares mean change of -2.80 compared to -1.82 vs. placebo, for a treatment difference of -0.98. This did not meet statistical significance (P = .15).

In the five participants who were LRP4-Ab seropositive, the mean MG-ADL total score change from baseline to week 4 was -2.8 (SD, 1.8). Comparison data vs placebo were not available due to the small sample size. 

Researchers deemed efgartigimod to be well-tolerated, with no new safety problems identified. In part A, treatment-emergent adverse events occurred in 62.1% of the efgartigimod group vs 49.2% of placebo recipients. Serious adverse effects occurred in 5.2% and 1.6% of the groups, respectively. 

Most adverse events were deemed mild to moderate, affecting less than 10% of the overall population. The most frequent were upper respiratory tract infection, nausea, headache, urinary tract infection, and fatigue. 

“We don’t see an increase in infections relative to what we have noted in the past with the use of this compound. We did have three deaths. Two were in part A — one in the efgartigimod group and one in the placebo group, not felt to be related to therapy — and then one in part B, potentially related to efgartigimod. But we don’t have additional data,” Howard said. 

The death in the part A efgartigimod group was due to MG crisis, and the death in the part A placebo group was due to large intestinal hemorrhage. The part B death was unexpected, and no autopsy was performed.

No changes in serum albumin or cholesterol levels were observed with efgartigimod.

Efgartigimod was approved by the FDA 2021 for AChR-positive gMG. Its manufacturer, argenx, plans to ask the FDA to expand the drug’s label to include AChR-Ab-seronegative gMG patients across all three subtypes.

Significant Improvements

Commenting on the findings for Medscape Medical News, Kavita M. Grover, MD, an associate professor of neurology at Henry Ford Health, Detroit, who was not involved in the research, said that the improvements in the MuSK-Ab seropositive participants are significant. For these patients, she said, “this drug will work well.”

She also highlighted that while MG-ADL changes in the triple-seronegative subgroup were not statistically significant at first, patients continued to improve in the open-label extension trial. 

Grover noted that patients should be counseled about how efgartigimod can lead to a higher rate of infections, including upper respiratory infections. However, she noted that most of the time such infections that do occur are mild to moderate, she noted. 

Argenx funded the study. Howard discloses relationships with Ad Scientiam, Alexion, AstraZeneca Rare Disease, argenx, Cartesian, Centers for Disease Control and Prevention, Merck EMD Serono, Myasthenia Gravis Foundation of America, Muscular Dystrophy Association, National Institutes of Health, NMD Pharma, UCB, AcademicCME, Amgen, Biohaven, CheckRare, CorEvitas, Curie.bio, Hansa Biopharma, H. Lundbeck A/S, Novartis Pharma, PeerView CME, Physicians’ Education Resource CME, PlatformQ CME, Regeneron, Sanofi US, Seismic Therapeutics, TG Therapeutics, and Toleranzia AB. Grover discloses a relationship with Johnson & Johnson. Her institution was to be an investigative site in the ADAPT SERON study but did not enroll anyone.