Gefurulimab, a novel bispecific nanobody that targets complement factor 5 (C5) delivers rapid and sustained clinical benefit in patients with anti–acetylcholine receptor antibody–positive (AChR-Ab+) generalized myasthenia gravis (gMG), as shown in the phase III PREVAIL trial.
PREVAIL met its primary endpoint, with Myasthenia Gravis Activities of Daily Living (MG-ADL) total score decreasing significantly more with gefurulimab vs placebo over 26 weeks of treatment (mean change, −4.2 vs −2.6; treatment difference, −1.6, 95 percent confidence interval [CI], −2.4 to −0.8; p<0.001). [JAMA Neurol 2026;doi:10.1001/jamaneurol.2026.2333]
Improvements in MG-ADL total score in the gefurulimab vs the placebo group were observed as early as week 1 (treatment difference, −1.3, 95 percent CI, −1.9 to −0.8; p<0.001) and sustained through week 26, reported lead author Dr Kelly Gwathmey from Virginia Commonwealth University in Richmond, Virginia, US, and colleagues.
Results for the key secondary endpoint of Quantitative Myasthenia Gravis (QMG) total score at week 26 also favoured gefurulimab. Mean QMG total score decreased by −4.5 in the gefurulimab group vs −2.4 in the placebo group (treatment difference, −2.1, 95 percent CI, −3.1 to −1.1; p<0.001).
Patients in the gefurulimab group vs the placebo group were more likely to achieve a reduction of ≥5 points in QMG total score (46.3 percent vs 25.2 percent; odds ratio [OR], 2.56, 95 percent CI, 1.42–4.62; p=0.002) and ≥3 points in MG-ADL total score (65.5 percent vs 52.2 percent; OR, 1.74, 95 percent CI, 1.03–2.93; p=0.04).
“The predefined response thresholds exceeded the established minimal clinically important difference for the respective scales. The significant difference in the responder rates between the gefurulimab and placebo groups underscores the robust symptom reduction achieved with gefurulimab,” Gwathmey and colleagues noted.
Self-administered regimen
As a nanobody, gefurulimab is administered via once-weekly subcutaneous self-injections. This convenient route of administration offers patients more autonomy and greater flexibility compared with currently available therapies, according to Gwathmey and colleagues.
“The bispecific design allows gefurulimab to bind to albumin and C5, thereby blocking C5 activation while leveraging albumin-mediated recycling to extend half-life and support the once-weekly dosing interval,” the authors said.
“Additionally, the binding sites for gefurulimab and immunoglobulin G on the FcRn differ, allowing for concomitant treatment with immunoglobulin, which is an important consideration for the treatment of MG. Several patients received immunoglobulin as chronic or rescue therapy during PREVAIL, without needing gefurulimab supplementation,” they continued.
Currently, there are only two nanobody-based therapies approved by the US FDA and the European Medicines Agency, indicated for the treatment of a rare haematologic disorder and advanced multiple myeloma.
“Gefurulimab has the potential to be the first therapeutic nanobody in neurology representing the next generation of antibody therapy,” Gwathmey and colleagues said.
Competitive positioning
In an accompanying editorial, Drs Christiane Schneider-Gold and Ralf Gold from the Ruhr University Bochum, Bochum, Germany, pondered the ultimate role of gefurulimab among existing treatments for gMG. [JAMA Neurol 2026;doi:10.1001/jamaneurol.2026.2329]
Schneider-Gold and Gold noted that the improvements in MG-ADL and QMG total scores seen with gefurulimab in PREVAIL were comparable with those reported for eculizumab, ravulizumab, and zilucoplan in their respective phase III trials. [Lancet Neurol 2017;16:976-986; NEJM Evid 2022;1:a2100066; Lancet Neurol 2023;22:395-406]
“It remains an interesting matter which position gefurulimab will eventually gain in the continuously evolving treatment landscape in gMG and among the group of complement inhibitors. It remains to be shown whether further nanobodies directed against other targets will follow in gMG therapy and for treatment of other neuroimmune diseases,” Schneider-Gold and Gold said.
“Meanwhile, more highly effective therapeutics are needed in MG to increase the potential of reducing permanent disability in severely afflicted patients,” they added.
The PREVAIL trial
PREVAIL was conducted at 113 sites in 20 countries, including Japan and China. The trial involved 260 adult patients (mean age 52.8 years, 60.4 percent female, 31.2 percent Asian) with AChR-Ab-positive gMG, a Myasthenia Gravis Foundation of America classification II through IV, and MG-ADL total score of ≥5.
The patients were randomly assigned to receive gefurulimab (n=131) or placebo (n=129) via once-weekly subcutaneous self-injection. Demographic and baseline clinical characteristics were balanced between the treatment groups and reflect the gMG population.
In terms of safety, “gefurulimab was generally well tolerated, with most adverse events (AEs) being mild or moderate in severity and a low dropout rate,” they added.
Treatment-emergent AEs occurred in 75.6 percent of patients in the gefurulimab group and 80.6 percent in the placebo group. The most common AEs were headache (9.9 percent), back pain (7.6 percent), and nasopharyngitis (6.9 percent) in the gefurulimab group and headache (12.4 percent), diarrhoea (8.5 percent), and upper respiratory tract infection (7.8 percent) in the placebo group.
Injection site reactions (ISRs) were reported in 9.9 percent and 3.1 percent of patients in the gefurulimab and placebo groups, respectively. Most ISRs (62 percent) occurred within the first 3 weeks of the trial, and the incidence decreased with subsequent injections. None of the patients discontinued treatment due to ISRs.
Serious AEs occurred in 9.2 percent of patients in the gefurulimab group and in 11.6 percent in the placebo group. One death was reported in each treatment group, but neither was considered related to the treatment.
Gwathmey and colleagues acknowledged that PREVAIL’s 6-month duration was insufficient to evaluate the long-term safety and efficacy of gefurulimab, but the open-label extension (OLE) for the trial is ongoing and is expected to provide evidence on the long-term clinical benefit and safety of gefurulimab.
“During the double-blind period, patients could continue previously prescribed MG medications provided the doses were stable and well tolerated. In the OLE, investigators may adjust the dose of concomitant medications,” the authors said.