This randomized clinical trial compares the novel dual-binding nanobody gefurulimab vs placebo for treating anti–acetylcholine receptor antibody–positive generalized myasthenia gravis.
Key Points
Question
Is gefurulimab a relatively safe and efficacious treatment for adults with anti–acetylcholine receptor antibody–positive (AChR-Ab+) generalized myasthenia gravis (gMG)?
Findings
In this randomized clinical trial in AChR-Ab+ gMG, gefurulimab treatment reduced Myasthenia Gravis Activities of Daily Living total score at week 26 compared with placebo with statistically significant treatment effect, achieving the primary end point for the study. The incidence of adverse events was similar between treatment groups.
Meaning
Gefurulimab, a novel dual-binding nanobody administered via weekly subcutaneous self-injection, demonstrated the potential to offer adults with AChR-Ab+ gMG an efficacious and convenient treatment option.
Abstract
Importance
Gefurulimab is a novel dual-binding nanobody that blocks complement component 5 activation. Complement activation is a key pathogenic mechanism in anti–acetylcholine receptor antibody–positive (AChR-Ab+) generalized myasthenia gravis (gMG).
Objective
To evaluate the efficacy and safety of gefurulimab in adults with AChR-Ab+ gMG.
Design, Setting, and Participants
This randomized clinical trial, PREVAIL, was a phase 3, double-blind, placebo-controlled study conducted at 113 sites in 20 countries. Patients were screened and randomized from November 2022 to November 2024; the randomized controlled treatment period was 26 weeks. Participants were adults (aged ≥18 years) with AChR-Ab+ gMG, a Myasthenia Gravis Foundation of America classification II through IV, and a Myasthenia Gravis Activities of Daily Living (MG-ADL) total score of 5 or higher.
Intervention
Gefurulimab or placebo via once-weekly subcutaneous self-injection.
Main Outcomes and Measures
The primary end point was change from baseline in MG-ADL total score at week 26. The key secondary end point was change from baseline in Quantitative Myasthenia Gravis (QMG) total score at week 26. Safety was also assessed.
Results
Of 405 patients screened, 145 were excluded; 260 met eligibility criteria and were randomized (gefurulimab, n = 131; placebo, n = 129); 249 patients completed the 26-week randomized controlled treatment period. The mean (SD) age was 52.8 (15.73) years; 157 (60.4%) patients were female and 103 (39.6%) were male. All primary and secondary end points were met with statistical significance. Improvements occurred within 1 week for MG-ADL score and 4 weeks for QMG score and were sustained through week 26. Least-squares mean change from baseline at week 26 for MG-ADL and QMG total scores for gefurulimab vs placebo were −4.2 vs −2.6 (treatment difference, −1.6; 95% CI, −2.4 to −0.8; P < .001) and −4.5 vs −2.4 (treatment difference, −2.1; 95% CI, −3.1 to −1.1; P < .001), respectively. The incidence of adverse events (AEs) was similar between groups. Most common treatment-emergent AEs with gefurulimab were injection site reactions, headache, back pain, and nasopharyngitis. No meningococcal infections were reported.
Conclusions and Relevance
Gefurulimab demonstrated both early and sustained clinical benefit in AChR-Ab+ gMG and was well tolerated, supporting its potential as a convenient, once-weekly, self-administered treatment regimen.
Trial Registration
ClinicalTrials.gov Identifier: NCT05556096
Introduction
Myasthenia gravis (MG), a rare, chronic autoimmune disease characterized by muscle weakness, has an estimated global prevalence ranging from 140 to 393 per million people. Approximately 85% of patients with generalized MG (gMG) have autoantibodies against the postsynaptic nicotinic acetylcholine receptor (AChR) at the neuromuscular junction on skeletal muscle. Binding of anti-AChR antibodies activates the complement pathway. Subsequent cleavage of complement component 5 (C5) initiates the terminal complement cascade and formation of the membrane attack complex, which can damage the postsynaptic muscle membrane and impair neuromuscular signal transmission. Terminal complement activation is a key pathogenic mechanism in anti–acetylcholine receptor antibody–positive (AChR-Ab+) gMG.
Several treatments are approved for AChR-Ab+ gMG, with different mechanisms of action. One of the established treatment approaches is C5 inhibition. Eculizumab and ravulizumab are monoclonal antibodies administered intravenously every 2 and 8 weeks, respectively. Zilucoplan, a macrocyclic peptide, is self-injected subcutaneously once daily. Other approaches include neonatal Fc receptor (FcRn) inhibitors such as efgartigimod and rozanolixizumab, which are administered intravenously or subcutaneously in intermittent treatment cycles, and nipocalimab, which is administered intravenously every 2 weeks. Additionally, inebilizumab, a CD19+ B-cell–depleting therapy, is administered intravenously every 6 months. Although these treatments are effective for AChR-Ab+ gMG, patients may benefit from new treatments with alternative administration options.
Gefurulimab, developed with the nanobody-based platform, may provide an alternative option. Nanobodies are single-domain antibodies derived from naturally occurring heavy-chain–only antibodies found in the sera of camelids. Compared with conventional antibodies, nanobodies have unique and advantageous properties, including small molecular size, high solubility, and tissue penetration, which make nanobodies attractive tools for developing therapeutic applications. Engineered fusion with albumin-binding units can be used to prolong systemic circulation and improve the pharmacokinetics to achieve long-lasting therapeutic effects. Gefurulimab comprises 2 variable domains of a heavy-chain (VHH), an N-terminal anti-albumin VHH and a C-terminal anti-C5 VHH, connected via a flexible linker, and blocks C5 activation by inhibiting its enzymatic cleavage (eFigure 1 in Supplement 2). This dual-binding nanobody has a low molecular weight, approximately 5 times lower than that of conventional antibodies, while maintaining high affinity for its targets, enabling concentration in small volumes suitable for subcutaneous self-injection. In addition to blocking C5 activation, the albumin-binding capacity of gefurulimab results in an extended half-life via FcRn recycling and allows once-weekly dosing.
Compared with the available therapies for gMG, the administration route and dosing regimen of gefurulimab may provide patients a convenient treatment option with predictable treatment schedule and greater autonomy. Here we report the results from the global phase 3 PREVAIL trial, which evaluated the safety and efficacy of gefurulimab in adults with AChR-Ab+ gMG.
Methods
Trial Design and Oversight
PREVAIL, a phase 3, randomized, double-blind, placebo-controlled trial, was conducted across 113 sites in 20 countries (Table 1 and the eAppendix in Supplement 2). PREVAIL included a screening period up to 4 weeks and a 26-week randomized controlled treatment (RCT) period, followed by an open-label extension (OLE) up to 202 weeks (eFigure 2 in Supplement 2). Patients were stratified by geographical region (North America, South America, Europe, Japan, China, rest of Asia-Pacific) and body weight (<80 kg and ≥80 kg) at baseline and were randomized 1:1 to receive weekly weight-based subcutaneous self-injection of gefurulimab or placebo with a prefilled syringe with a needle safety device (ClinicalTrials.gov NCT05556096).
Table 1. Demographics and Baseline Clinical Characteristics.
| Characteristica | No. (%) | ||
|---|---|---|---|
| Gefurulimab (n = 131) | Placebo (n = 129) | Total (N = 260) | |
| Sex | |||
| Female | 78 (59.5) | 79 (61.2) | 157 (60.4) |
| Male | 53 (40.5) | 50 (38.8) | 103 (39.6) |
| Raceb | |||
| Asian | 43 (32.8) | 38 (29.5) | 81 (31.2) |
| Black or African American | 3 (2.3) | 3 (2.3) | 6 (2.3) |
| White | 69 (52.7) | 74 (57.4) | 143 (55.0) |
| Multiple | 2 (1.5) | 0 | 2 (0.8) |
| Unknown or not reported | 14 (10.7) | 13 (10.1) | 27 (10.4) |
| Other | 0 | 1 (0.8) | 1 (0.4) |
| Region | |||
| North America | 16 (12.2) | 15 (11.6) | 31 (11.9) |
| South America | 10 (7.6) | 10 (7.8) | 20 (7.7) |
| Europe | 57 (43.5) | 56 (43.4) | 113 (43.5) |
| Japan | 7 (5.3) | 8 (6.2) | 15 (5.8) |
| China | 16 (12.2) | 15 (11.6) | 31 (11.9) |
| Rest of Asia-Pacific | 25 (19.1) | 25 (19.4) | 50 (19.2) |
| Age at first dose of trial intervention, mean (SD), y | 53.0 (14.42) | 52.7 (17.00) | 52.8 (15.73) |
| Baseline MGFA Clinical Classification | |||
| Class IIa | 22 (16.8) | 29 (22.5) | 51 (19.6) |
| Class IIb | 26 (19.8) | 16 (12.4) | 42 (16.2) |
| Class IIIa | 52 (39.7) | 54 (41.9) | 106 (40.8) |
| Class IIIb | 24 (18.3) | 23 (17.8) | 47 (18.1) |
| Class IVa | 4 (3.1) | 4 (3.1) | 8 (3.1) |
| Class IVb | 3 (2.3) | 3 (2.3) | 6 (2.3) |
| Baseline MG-ADL total score, mean (SD)c | 9.0 (2.29) | 9.0 (2.03) | 9.0 (2.16) |
| Baseline QMG total score, mean (SD)d | 14.9 (4.38) | 14.7 (4.39) | 14.8 (4.37) |
| Baseline MGC total score, mean (SD)e | 16.4 (5.32) | 16.1 (5.39) | 16.2 (5.35) |
| Age at MG diagnosis, mean (SD), y | 43.8 (17.55) | 44.6 (19.37)f | 44.2 (18.44)g |
| Time from MG diagnosis to first dose of trial intervention, mean (SD), y | 9.2 (8.45) | 8.2 (8.79)f | 8.7 (8.62)g |
| Received corticosteroids at baseline | 84 (64.1) | 92 (71.3) | 176 (67.7) |
| Received nonsteroidal immunosuppressive therapy at baselineh | 79 (60.3) | 72 (55.8) | 151 (58.1) |
Abbreviations: MG, myasthenia gravis; MG-ADL, Myasthenia Gravis Activities of Daily Living; MGC, Myasthenia Gravis Composite; MGFA, Myasthenia Gravis Foundation of America; QMG, Quantitative Myasthenia Gravis.
Baseline is defined as the last available assessment value before the first dose of trial intervention. Percentages are based on the total number of patients in each group.
Patient-reported race was captured to assess the diversity of the trial. The patient who selected “other” specified Hispanic.
MG-ADL total score ranges from 0 (least severe) to 24 (most severe).
QMG total score ranges from 0 (least severe) to 39 (most severe).
MGC total score ranges from 0 (least severe) to 50 (most severe).
n = 128.
n = 259.
Includes azathioprine, cyclosporine, methotrexate, mycophenolate mofetil, and tacrolimus.
The trial protocol (available with the statistical analysis plan in Supplement 1) was approved by local independent institutional review boards and all required regulatory or health authorities. All patients provided written, informed consent prior to screening. The trial was conducted in accordance with the principles of the Declaration of Helsinki, Good Clinical Practice guidelines of the International Council for Harmonisation, and all applicable laws and regulations. The reporting of the study adhered to the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.
Patients
Eligibility criteria were age 18 years or older, documented diagnosis of gMG at 90 days or longer before screening, a positive serological test for anti-AChR autoantibodies at screening, Myasthenia Gravis Foundation of America (MGFA) classification II to IV at screening, and Myasthenia Gravis Activities of Daily Living (MG-ADL) total score 5 or higher at screening and on day 1 before randomization. Continued use of previously prescribed therapies, including corticosteroids, nonsteroidal immunosuppressants, and intravenous immunoglobulin or subcutaneous immunoglobulin was allowed, provided the doses remained stable and well tolerated. Patients were excluded if they received prior treatment with a complement or FcRn inhibitor within less than 5 half-lives before day 1. Patients must have been vaccinated against Neisseria meningitidis within 3 years before day 1, following local and national guidelines. Patients who did not meet this requirement were vaccinated against N meningitidis before receiving the first dose of trial intervention, and if day 1 occurred less than 2 weeks after vaccination, patients received prophylactic antibiotics until 2 weeks after vaccination. Full details of the eligibility criteria are provided in Supplement 1. Patient-reported race was captured to assess the diversity of the trial.
Trial Procedures
Gefurulimab or matching placebo was administered by the patient or caregiver subcutaneously via a prefilled syringe. Dosing was based on body weight (eTable 1 in Supplement 2). Patients received an initial loading dose of gefurulimab (600 or 900 mg) or placebo at baseline (day 1) followed by maintenance doses of gefurulimab (300 or 600 mg) or placebo on day 8 and every week thereafter for 26 weeks. Rescue therapy was permitted in the event of a clinically significant MG deterioration or if the patient’s health would be in jeopardy without such therapy (eMethods in Supplement 2).
End Points
Efficacy was assessed using the following validated outcome measures: MG-ADL, Quantitative Myasthenia Gravis (QMG), and Myasthenia Gravis Composite (MGC) scales. Additional details on outcome measures are provided in the eMethods in Supplement 2.
The primary end point was change from baseline in MG-ADL total score at week 26. The key secondary end point was change from baseline in QMG total score at week 26. Other secondary end points included the responder analysis of QMG total score (≥5-point reduction in QMG total score from baseline to week 26) and MG-ADL total score (≥3-point reduction in MG-ADL total score from baseline to week 26), change from baseline in MGC total score at week 26, and change from baseline in QMG total score at week 4.
Adverse events (AEs) were assessed in all patients who received 1 or more dose of gefurulimab or placebo and were categorized according to incidence, type, severity, and relationship with the trial intervention. AEs of special interest included meningococcal infections.
Statistical Analysis
Sample size estimation was based on the primary end point and results from the CHAMPION MG trial, which evaluated the efficacy and safety of ravulizumab in adults with AChR-Ab+ gMG. Assuming gefurulimab would provide a similar result to ravulizumab and 10% attrition, a sample size of 254 patients was required to ensure approximately 90% power at a 2-sided type I error rate (α) of .05 to reject the null hypothesis of no treatment effect, based on change from baseline in MG-ADL total score at week 26.
For the primary end point and continuous secondary end points related to change from baseline, a mixed-effects model for repeated measures was used. Covariates included fixed categorical effect of treatment, randomization stratification factors of geographical region and baseline body weight (<80 and ≥80 kg), and fixed effects of baseline score, trial visit, and treatment × trial visit interaction. Missing data were not imputed and assumed to be missing at random. All randomly assigned patients who received at least 1 dose of trial intervention were analyzed. All data collected were included in the analysis regardless of intercurrent events such as use of rescue therapy and discontinuation of trial intervention. The responder end points were analyzed using a generalized linear mixed model.
The overall 2-sided type I error was controlled at .05 for the primary and secondary end points. The primary and key secondary end points were tested using a fixed-sequence hierarchical testing procedure, with the primary end point tested first at an α of .05 followed by the key secondary end point. If both the primary and key secondary end points were statistically significant (P < .05), the remaining secondary end points were tested using the Holm-Bonferroni procedure.
Sensitivity analyses were performed for the primary end point to explore the influence of missing data and on the per-protocol set for both the primary and secondary end points. Further details regarding the statistical analysis are provided in the eMethods in Supplement 2.
Results
Patients
Between November 2022 and November 2024, 405 patients were screened and 260 were randomized: 131 patients (50.4%) received gefurulimab and 129 (49.6%) received placebo (Figure 1). Demographic and baseline clinical characteristics were balanced between groups and reflect the gMG population (Table 1 and eTable 2 in Supplement 2). Most patients were female (157 [60.4%] vs 103 [39.6%] male) and either Asian (81 [31.2%]) or White (143 [55.0%], compared with 6 [2.3%] who were Black or African American and 30 [11.5%] who reported multiple races, unknown race, or other or did not report race). The mean (SD) ages at first dose of trial intervention and MG diagnosis were 52.8 (15.73) and 44.2 (18.44) years, respectively. The mean (SD) baseline MG-ADL and QMG total scores were 9.0 (2.16) and 14.8 (4.37), respectively, including 41 (15.8%) patients with 50% or more of baseline MG-ADL total score attributed to the ocular subdomain. A small proportion of patients used prior complement inhibitor (2.3%) or FcRn inhibitor (9.6%) within 2 years before screening; all occurred more than 5 half-lives before day 1. At trial initiation, 108 (82.4%) patients in the gefurulimab group and 107 (82.9%) in the placebo group were receiving any immunosuppressive therapy. Further details on concomitant therapy use during the trial are provided in eTable 3 in Supplement 2.
Figure 1. Flow Diagram of PREVAIL Disposition.
OLE denotes open-label extension.
aRandomization stratified by body weight (<80 kg and ≥80 kg) and geographical region (North America, South America, Europe, Japan, China, rest of Asia-Pacific).
This article describes results from the 26-week RCT period. Overall, 249 patients (95.8%) completed the 26 weeks. Discontinuation rates were similar between gefurulimab (4 patients [3.1%]) and placebo (7 patients [5.4%]).
Efficacy End Points
Primary End Point
The least-squares (LS) mean MG-ADL total score change from baseline to week 26 was −4.2 (95% CI, −4.7 to −3.6) in the gefurulimab group and −2.6 (95% CI, −3.1 to −2.0) in the placebo group (treatment difference, −1.6; 95% CI, −2.4 to −0.8; P < .001) (Figure 2A and Table 2). Improvements in MG-ADL total score in the gefurulimab group were observed at week 1 (treatment difference, −1.3; 95% CI, −1.9 to −0.8; P < .001) and sustained through week 26.
Figure 2. Plots and Bar Charts of Trial Outcome Measures Over Time and Prespecified Responder Analyses at Week 26.
A, Changes from baseline (BL) in Myasthenia Gravis Activities of Daily Living (MG-ADL) total score over time. B, Changes from BL in Quantitative Myasthenia Gravis (QMG) total score over time. C, Adjusted percentage of patients who achieved various point reductions in QMG total score at week 26. D, Adjusted percentage of patients who achieved various point reductions in MG-ADL total score at week 26. E, Changes from BL in Myasthenia Gravis Composite (MGC) total score over time. For panels A, B, and E, estimates are based on a mixed-effects model for repeated measures that includes treatment group; stratification factors of geographical region and BL body weight category; MG-ADL, QMG, or MGC total score at BL; trial visit; and treatment group × trial visit interaction. An unstructured covariance structure was used. For panels C and D, estimates are based on a generalized linear mixed model that includes treatment group; stratification factors of geographical region and BL body weight category; MG-ADL or QMG total score at BL; study trial; and treatment group × trial visit interaction. An autoregressive covariance structure was used; if the model did not converge with autoregressive, a compound symmetry covariance structure was used. LS indicates least squares.
aP < .001; 2-sided nominal P values are reported for the comparison of change from BL between treatment groups for weeks 1 to 23 for MG-ADL, weeks 8 to 20 for QMG, and 4 to 20 for MGC scores.
bDefined as the last available assessment value before the first dose of trial intervention.
cP = .002 for the prespecified secondary end point of treatment response based on a ≥5-point reduction in QMG total score.
dP = .04 for the prespecified secondary end point of treatment response based on a ≥3-point reduction in MG-ADL total score.
Table 2. Efficacy End Point Analyses.
| End point | Gefurulimab (n = 131) | Placebo (n = 129) | P value |
|---|---|---|---|
| Primary end point: change from baseline in MG-ADL total score at week 26a | |||
| Least-squares mean (95% CI) | −4.2 (−4.7 to −3.6) | −2.6 (−3.1 to −2.0) | |
| Treatment difference (95% CI) | −1.6 (−2.4 to −0.8) | <.001 | |
| Key secondary end point: change from baseline in QMG total score at week 26a | |||
| Least-squares mean (95% CI) | −4.5 (−5.2 to −3.8) | −2.4 (−3.1 to −1.7) | |
| Treatment difference (95% CI) | −2.1 (−3.1 to −1.1) | <.001 | |
| Secondary end points | |||
| QMG score, ≥5-point reduction at week 26b | |||
| Adjusted % | 46.3 | 25.2 | |
| Odds ratio (95% CI) | 2.56 (1.42 to 4.62) | .002 | |
| MG-ADL score, ≥3-point reduction at week 26b | |||
| Adjusted % | 65.5 | 52.2 | |
| Odds ratio (95% CI) | 1.74 (1.03 to 2.93) | .04 | |
| Change from baseline in MGC total score at week 26a | |||
| Least-squares mean (95% CI) | −7.8 (−8.8 to −6.8) | −4.7 (−5.7 to −3.8) | |
| Treatment difference (95% CI) | −3.1 (−4.4 to −1.7) | <.001 | |
| Change from baseline in QMG total score at week 4a | |||
| Least-squares mean (95% CI) | −3.3 (−3.9 to −2.7) | −1.5 (−2.0 to −1.0) | |
| Treatment difference (95% CI) | −1.8 (−2.5 to −1.1) | <.001 |
Abbreviations: MGC, Myasthenia Gravis Composite; MG-ADL, Myasthenia Gravis Activities of Daily Living; QMG, Quantitative Myasthenia Gravis.
Estimates are based on mixed-effects model for repeated measures that includes treatment group; stratification factors of region and baseline body weight category; MG-ADL, QMG, and MGC total scores at baseline; trial visit; and treatment group × trial visit interaction. An unstructured covariance structure was used.
Estimates are based on a generalized linear mixed model that includes treatment group, stratification factors of region and baseline body weight category; MG-ADL and QMG total score at baseline; trial visit; and treatment group × trial visit interaction. An autoregressive covariance structure was used.
Key Secondary End Point
The LS mean QMG total score change from baseline to week 26 was −4.5 (95% CI, −5.2 to −3.8) in the gefurulimab group and −2.4 (95% CI, −3.1 to −1.7) in the placebo group (treatment difference, −2.1; 95% CI, −3.1 to −1.1; P < .001) (Figure 2B).
Secondary End Points
At week 26, 58 of 124 patients (46.8%) in the gefurulimab group and 33 of 118 patients (28.0%) in the placebo group achieved a reduction of 5 or more points in QMG total score (adjusted percentage, 46.3% vs 25.2%, respectively; odds ratio [OR], 2.56; 95% CI, 1.42 to 4.62; P = .002) (Figure 2C). At week 26, 82 of 125 patients (65.6%) in the gefurulimab group and 63 of 121 patients (52.1%) in the placebo group achieved a reduction of 3 or more points in MG-ADL total score (adjusted percentage, 65.5% vs 52.2%, respectively; OR, 1.74; 95% CI, 1.03 to 2.93; P = .04) (Figure 2D).
The LS mean MGC total score change from baseline to week 26 was −7.8 (95% CI, −8.8 to −6.8) in the gefurulimab group and −4.7 (95% CI, −5.7 to −3.8) in the placebo group (treatment difference, −3.1; 95% CI, −4.4 to −1.7; P < .001) (Figure 2E). Improvements in MGC total score in the gefurulimab group were observed at week 4 (the first assessment after treatment initiation) and sustained through 26 weeks of treatment.
Improvements in QMG total score in the gefurulimab group were observed at week 4 (the first assessment after treatment initiation; treatment difference, −1.8; 95% CI, −2.5 to −1.1; P < .001) and sustained through week 26.
During the RCT period, 7 patients (5.3%) in the gefurulimab group and 16 patients (12.4%) in the placebo group received rescue therapy.
Safety
The proportion of patients who experienced 1 or more treatment-emergent AE was similar between the treatment groups (Table 3 and eTable 4 in Supplement 2): 99 patients (75.6%) in the gefurulimab group and 104 patients (80.6%) in the placebo group. Most events were mild to moderate in severity. The 3 most common treatment-emergent AEs by preferred term were headache (9.9%), back pain (7.6%), and nasopharyngitis (6.9%) in the gefurulimab group and headache (12.4%), diarrhea (8.5%), and upper respiratory tract infection (7.8%) in the placebo group. Injection site reactions (ISRs), for example, injection site pain, erythema, pruritus, and others combined, were reported in 13 patients (9.9%) and 4 patients (3.1%) in the gefurulimab and placebo groups, respectively, with most (62%) first-onset ISRs occurring within the first 3 weeks of the trial and decreasing with subsequent injections. No patients discontinued the trial due to ISRs.
Table 3. Summary of Treatment-Emergent Adverse Events.
| Event | Gefurulimab (n = 131; PY = 65.4) | Placebo (n = 129; PY = 64.5) | ||
|---|---|---|---|---|
| Patients, No. (%) | No. of events | Patients, No. (%) | No. of events | |
| Any AE | 99 (75.6) | 411 | 104 (80.6) | 398 |
| Related to trial intervention | 36 (27.5) | 88 | 36 (27.9) | 73 |
| Related to devicea | 0 | 0 | 0 | 0 |
| Leading to discontinuation of trial intervention | 1 (0.8)b | 1 | 1 (0.8)c | 1 |
| AE of special interest (meningococcal infection) | 0 | 0 | 0 | 0 |
| Injection site reactionsd | 13 (9.9) | 32 | 4 (3.1) | 4 |
| By severity | ||||
| Grade 1 | 75 (57.3) | 219 | 79 (61.2) | 205 |
| Grade 2 | 57 (43.5) | 171 | 67 (51.9) | 157 |
| Grade 3 | 13 (9.9) | 17 | 16 (12.4) | 25 |
| Grade 4 | 3 (2.3) | 3 | 5 (3.9) | 10 |
| Grade 5 | 1 (0.8) | 1 | 1 (0.8) | 1 |
| Any serious AE | 12 (9.2) | 14 | 15 (11.6) | 30 |
| Related to trial intervention | 0 | 0 | 2 (1.6) | 2 |
| Leading to discontinuation of trial intervention | 1 (0.8)b | 1 | 0 | 0 |
| Death | 1 (0.8)e | 1 | 1 (0.8)f | 1 |
| AE reported in ≥5% of patients in either groupg | ||||
| Headache | 13 (9.9) | 18 | 16 (12.4) | 20 |
| Back pain | 10 (7.6) | 11 | 2 (1.6) | 3 |
| Nasopharyngitis | 9 (6.9) | 13 | 9 (7.0) | 9 |
| Upper respiratory tract infection | 8 (6.1) | 10 | 10 (7.8) | 11 |
| Diarrhea | 8 (6.1) | 9 | 11 (8.5) | 12 |
| Urinary tract infection | 7 (5.3) | 8 | 4 (3.1) | 5 |
| COVID-19 | 5 (3.8) | 5 | 9 (7.0) | 10 |
| Dizziness | 2 (1.5) | 2 | 8 (6.2) | 13 |
Abbreviations: AE, adverse event; PY, patient-years.
Includes device malfunction, inadequate instructions for use or product label, use error, and misuse or abnormal use as determined by the investigator.
Withdrawal due to suicide attempt.
Withdrawal due to vitamin D deficiency.
Includes the following preferred terms: injection site erythema, injection site pain, injection site swelling, administration site rash, injection site pruritus, injection site reaction, injection site hematoma, erythema, rash, skin burning sensation, and skin irritation.
Due to dengue fever; considered unrelated to the trial intervention.
Due to metabolic acidosis from complications of multiorgan failure; considered unrelated to the trial intervention.
By preferred term.
Serious AEs were reported in 12 patients (9.2%) in the gefurulimab group and 15 patients (11.6%) in the placebo group. No events in the gefurulimab group and 2 events (Bacillus bacteremia, herpes zoster) in the placebo group were considered related to the trial intervention (eTable 5 in Supplement 2). No AEs of special interest or AEs associated with use of the device were reported. One death occurred in each group; neither was considered related to the trial intervention. The death in the gefurulimab group was due to dengue fever in the context of a local dengue endemicity, and the primary cause of the death in the placebo group was metabolic acidosis due to complications of multiorgan failure.
Discussion
Gefurulimab met all primary and secondary end points in this phase 3 trial, demonstrating its efficacy for the treatment of adults with AChR-Ab+ gMG. Clinically meaningful improvements in MG-ADL, QMG, and MGC total scores were observed as early as the first assessment after treatment initiation (week 1 for MG-ADL and week 4 for QMG and MGC) and sustained through week 26, demonstrating an early onset of action and continued treatment effect. In the gefurulimab group, the LS mean change from baseline in MG-ADL total score at week 26 was −4.2, with 73.1% of patients achieving a 2-point or more improvement on the MG-ADL scale (the minimal clinically important difference [MCID]). Similarly, the LS mean change from baseline in QMG total score at week 26 was −4.5 in the gefurulimab group, with 66.9% of patients achieving the MCID of a 3-point or more improvement on the QMG scale. These results confirm clinically meaningful improvements in both patient-reported (MG-ADL) and investigator-assessed (QMG) outcome measures. A greater proportion of patients in the gefurulimab group achieved a 3-point or greater reduction in MG-ADL total score or 5-point or greater reduction in QMG total score in the responder analyses. These predefined response thresholds exceeded the established MCID 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.
Results from this trial demonstrate a favorable clinical profile for the C5-inhibiting nanobody gefurulimab. These findings, along with clinical and real-world evidence from approved C5 inhibitors, reinforce the predominant role of complement activation in the pathogenesis of gMG and support C5 inhibition as an effective therapeutic approach for this disease. While cross-trial comparisons should be interpreted with caution because of differences in trial design, the treatment effect of gefurulimab fell within the range of MG-ADL improvements reported in the phase 3 trials of advanced gMG therapies currently available. Gefurulimab also showed an early onset of efficacy consistent with other complement inhibitors.
Gefurulimab was generally well tolerated, with most AEs being mild or moderate in severity and a low dropout rate. The safety profile was comparable with eculizumab and ravulizumab, with no new safety signals. Similar to other trials involving subcutaneously administered biologics, ISRs in this trial were more often reported for gefurulimab than placebo. However, the incidence of reported ISRs decreased over time, and no participant discontinued gefurulimab treatment because of ISRs. No meningococcal infections were reported in either group.
The nanobody-based platform supports the development of gefurulimab with a lower molecular weight than conventional antibodies, enabling subcutaneous self-administration. 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. Collectively, these design features render gefurulimab a convenient treatment option offering patients more autonomy and greater flexibility compared with currently available therapies. 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.
While many nanobody-based therapies are being assessed in clinical trials, to date, only 2 are approved by the US Food and Drug Administration and the European Medicines Agency for a rare hematologic disorder and advanced multiple myeloma. Gefurulimab has the potential to be the first therapeutic nanobody in neurology representing the next generation of antibody therapy.
Strengths and Limitations
PREVAIL is one of the largest phase 3 studies in gMG with 260 patients enrolled from diverse regions. Patients had disease manifestations ranging from mild or moderate to severe symptoms. Therefore, the trial outcomes are likely applicable to the wider population with AChR-Ab+ gMG. While slight differences in a few baseline characteristics were observed between the 2 groups, such as the incidence of ocular MG as the first MG clinical presentation, thymectomy, and use of immunoglobulin therapy, these differences are unlikely to impact the overall results.
One limitation of this study was that the data were from the 6 months of RCT, which is insufficient to evaluate the long-term safety and efficacy of gefurulimab. The OLE for PREVAIL is ongoing and is expected to provide evidence about the long-term clinical benefit and safety of gefurulimab. During the RCT 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. Another limitation is that despite a diverse population of patients with gMG enrolled, there were few Black or African American patients enrolled.
Conclusions
Results from the PREVAIL trial demonstrate that the novel dual-binding nanobody gefurulimab is efficacious and well tolerated in adults with AChR-Ab+ gMG. With the advantage of self-administered subcutaneous weekly dosing, gefurulimab has the potential to offer patients with AChR-Ab+ gMG an effective and convenient option.
Trial protocol and statistical analysis plan
eAppendix. PREVAIL trial investigators
eMethods
eFigure 1. Key attributes of gefurulimab compared with conventional antibodies
eFigure 2. Trial design
eTable 1. Weight-based dosage regimen of gefurulimab in PREVAIL
eTable 2. Additional baseline patient demographics and clinical characteristics
eTable 3. Concomitant myasthenia gravis therapies used during the randomized controlled treatment period
eTable 4. Treatment-emergent adverse events during the randomized controlled trial period, by worst severity
eTable 5. Serious adverse events considered by the trial investigator to be related to trial agent
eReferences
Data sharing statement
References
- 1.Lai CH, Tseng HF. Nationwide population-based epidemiological study of myasthenia gravis in taiwan. Neuroepidemiology. 2010;35(1):66-71. doi: 10.1159/000311012 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Westerberg E, Punga AR. Epidemiology of myasthenia gravis in Sweden 2006-2016. Brain Behav. 2020;10(11):e01819. doi: 10.1002/brb3.1819 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Antonini G, Habetswallner F, Inghilleri M, et al. ; LHU study group . Real world study on prevalence, treatment and economic burden of myasthenia gravis in Italy. Heliyon. 2023;9(6):e16367. doi: 10.1016/j.heliyon.2023.e16367 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Mevius A, Jöres L, Biskup J, et al. Epidemiology and treatment of myasthenia gravis: a retrospective study using a large insurance claims dataset in Germany. Neuromuscul Disord. 2023;33(4):324-333. doi: 10.1016/j.nmd.2023.02.002 [DOI] [PubMed] [Google Scholar]
- 5.Saccà F, Salort-Campana E, Jacob S, Cortés-Vicente E, Schneider-Gold C. Refocusing generalized myasthenia gravis: patient burden, disease profiles, and the role of evolving therapy. Eur J Neurol. 2024;31(6):e16180. doi: 10.1111/ene.16180 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Gilhus NE, Tzartos S, Evoli A, Palace J, Burns TM, Verschuuren JJGM. Myasthenia gravis. Nat Rev Dis Primers. 2019;5(1):30. doi: 10.1038/s41572-019-0079-y [DOI] [PubMed] [Google Scholar]
- 7.Gilhus NE. Myasthenia gravis. N Engl J Med. 2016;375(26):2570-2581. doi: 10.1056/NEJMra1602678 [DOI] [PubMed] [Google Scholar]
- 8.Rodrigues E, Umeh E, Aishwarya, Navaratnarajah N, Cole A, Moy K. Incidence and prevalence of myasthenia gravis in the United States: a claims-based analysis. Muscle Nerve. 2024;69(2):166-171. doi: 10.1002/mus.28006 [DOI] [PubMed] [Google Scholar]
- 9.Vincent A, Newsom-Davis J. Acetylcholine receptor antibody as a diagnostic test for myasthenia gravis: results in 153 validated cases and 2967 diagnostic assays. J Neurol Neurosurg Psychiatry. 1985;48(12):1246-1252. doi: 10.1136/jnnp.48.12.1246 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Howard JF Jr. Myasthenia gravis: the role of complement at the neuromuscular junction. Ann N Y Acad Sci. 2018;1412(1):113-128. doi: 10.1111/nyas.13522 [DOI] [PubMed] [Google Scholar]
- 11.Hehir MK, Silvestri NJ. Generalized myasthenia gravis: classification, clinical presentation, natural history, and epidemiology. Neurol Clin. 2018;36(2):253-260. doi: 10.1016/j.ncl.2018.01.002 [DOI] [PubMed] [Google Scholar]
- 12.Michailidou I, Patsiarika A, Kesidou E, et al. The role of complement in the immunopathogenesis of acetylcholine receptor antibody-positive generalized myasthenia gravis: bystander or key player? Front Immunol. 2025;16:1526317. doi: 10.3389/fimmu.2025.1526317 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Meriggioli MN, Sanders DB. Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol. 2009;8(5):475-490. doi: 10.1016/S1474-4422(09)70063-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Soliris (eculizumab). Prescribing information. Alexion Pharmaceuticals; 2025.
- 15.Ultomiris (ravulizumab). Prescribing information. Alexion Pharmaceuticals; 2025.
- 16.Zilbrysq (zilucoplan). Prescribing information. UCB; 2026.
- 17.Imaavy (nipocalimab-aahu). Prescribing information. Janssen Biotech; 2025.
- 18.Vyvgart (efgartigimod alfa-fcab). Prescribing information. argenx US; 2025.
- 19.Vyvgart hytrulo (efgartigimod alfa and hyaluronidase-qcfc). Prescribing information. argenx US; 2026.
- 20.Rystiggo (rozanolixizumab-noli). Prescribing information. UCB; 2025.
- 21.Uplizna (inebilizumab-cdon). Prescribing information. Amgen; 2025.
- 22.Muppidi S, Utsugisawa K, Benatar M, et al. ; Regain Study Group . Long-term safety and efficacy of eculizumab in generalized myasthenia gravis. Muscle Nerve. 2019;60(1):14-24. doi: 10.1002/mus.26447 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Vu T, Meisel A, Mantegazza R, et al. Terminal complement inhibitor ravulizumab in generalized myasthenia gravis. NEJM Evid. 2022;1(5):EVIDoa2100066. doi: 10.1056/EVIDoa2100066 [DOI] [PubMed] [Google Scholar]
- 24.Howard JF Jr, Bresch S, Genge A, et al. ; RAISE Study Team . Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Neurol. 2023;22(5):395-406. doi: 10.1016/S1474-4422(23)00080-7 [DOI] [PubMed] [Google Scholar]
- 25.Bril V, Drużdż A, Grosskreutz J, et al. ; MG0003 study team . Safety and efficacy of rozanolixizumab in patients with generalised myasthenia gravis (MycarinG): a randomised, double-blind, placebo-controlled, adaptive phase 3 study. Lancet Neurol. 2023;22(5):383-394. doi: 10.1016/S1474-4422(23)00077-7 [DOI] [PubMed] [Google Scholar]
- 26.Howard JF Jr, Bril V, Vu T, et al. ; ADAPT Investigator Study Group . 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 [DOI] [PubMed] [Google Scholar]
- 27.Antozzi C, Vu T, Ramchandren S, et al. ; Vivacity-MG3 Study Group . Safety and efficacy of nipocalimab in adults with generalised myasthenia gravis (Vivacity-MG3): a phase 3, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2025;24(2):105-116. doi: 10.1016/S1474-4422(24)00498-8 [DOI] [PubMed] [Google Scholar]
- 28.Nowak RJ, Benatar M, Ciafaloni E, et al. ; MINT Investigators . A phase 3 trial of inebilizumab in generalized myasthenia gravis. N Engl J Med. 2025;392(23):2309-2320. doi: 10.1056/NEJMoa2501561 [DOI] [PubMed] [Google Scholar]
- 29.Jindal S, Pedersen DV, Gera N, et al. Characterization of the bispecific VHH antibody gefurulimab (ALXN1720) targeting complement component 5, and designed for low volume subcutaneous administration. Mol Immunol. 2024;165:29-41. doi: 10.1016/j.molimm.2023.12.004 [DOI] [PubMed] [Google Scholar]
- 30.Blank L, Pander G, Mühlberg E, Mier W, Uhl P. Exploiting the unique properties of nanobodies: enhancing therapeutics, drug delivery, and targeted diagnostics. Drug Discov Today. 2025;30(12):104524. doi: 10.1016/j.drudis.2025.104524 [DOI] [PubMed] [Google Scholar]
- 31.Kunz S, Durandy M, Seguin L, Feral CC. Nanobody® molecule, a giga medical tool in nanodimensions. Int J Mol Sci. 2023;24(17):13229. doi: 10.3390/ijms241713229 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Shepard HM, Phillips GL, D Thanos C, Feldmann M. Developments in therapy with monoclonal antibodies and related proteins. Clin Med (Lond). 2017;17(3):220-232. doi: 10.7861/clinmedicine.17-3-220 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Hopewell S, Chan A, Collins GS, et al. CONSORT 2025 statement: updated guideline for reporting randomized trials. JAMA. 2025;333(22):1998-2005. doi: 10.1001/jama.2025.4347 [DOI] [PubMed] [Google Scholar]
- 34.Wolfe GI, Herbelin L, Nations SP, Foster B, Bryan WW, Barohn RJ. Myasthenia gravis activities of daily living profile. Neurology. 1999;52(7):1487-1489. doi: 10.1212/WNL.52.7.1487 [DOI] [PubMed] [Google Scholar]
- 35.Barohn RJ, McIntire D, Herbelin L, Wolfe GI, Nations S, Bryan WW. Reliability testing of the quantitative myasthenia gravis score. Ann N Y Acad Sci. 1998;841:769-772. doi: 10.1111/j.1749-6632.1998.tb11015.x [DOI] [PubMed] [Google Scholar]
- 36.Burns TM, Conaway M, Sanders DB; MG Composite and MG-QOL15 Study Group . The MG Composite: a valid and reliable outcome measure for myasthenia gravis. Neurology. 2010;74(18):1434-1440. doi: 10.1212/WNL.0b013e3181dc1b1e [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Holm S. A simple sequentially rejective multiple test procedure. Scand J Stat Theory Appl. 1979;6(2):65-70. [Google Scholar]
- 38.Muppidi S, Wolfe GI, Conaway M, Burns TM; MG Composite and MG-QOL15 Study Group . MG-ADL: still a relevant outcome measure. Muscle Nerve. 2011;44(5):727-731. doi: 10.1002/mus.22140 [DOI] [PubMed] [Google Scholar]
- 39.Katzberg HD, Barnett C, Merkies IS, Bril V. Minimal clinically important difference in myasthenia gravis: outcomes from a randomized trial. Muscle Nerve. 2014;49(5):661-665. doi: 10.1002/mus.23988 [DOI] [PubMed] [Google Scholar]
- 40.Vu TH, Mantegazza R, Annane D, et al. ; CHAMPION MG Study Group . Long-term efficacy and safety of ravulizumab in adults with anti-acetylcholine receptor antibody-positive generalized myasthenia gravis: final results from the phase 3 CHAMPION MG open-label extension. Eur J Neurol. 2025;32(4):e70158. doi: 10.1111/ene.70158 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Howard JF Jr, Bresch S, Farmakidis C, et al. ; RAISE-XT Study Team . Long-term safety and efficacy of zilucoplan in patients with generalized myasthenia gravis: interim analysis of the RAISE-XT open-label extension study. Ther Adv Neurol Disord. 2024;17:17562864241243186. doi: 10.1177/17562864241243186 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Howard JF Jr, Utsugisawa K, Benatar M, et al. ; REGAIN Study Group . Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol. 2017;16(12):976-986. doi: 10.1016/S1474-4422(17)30369-1 [DOI] [PubMed] [Google Scholar]
- 43.Khani-Habibabadi F, Roy B, Pham MC, et al. AChR autoantibody pathogenic properties are heterogeneously distributed and undergo temporal changes among patients with myasthenia gravis. Neurol Neuroimmunol Neuroinflamm. 2025;12(5):e200436. doi: 10.1212/NXI.0000000000200436 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Zhi L, Liu D, Shameem M. Injection site reactions of biologics and mitigation strategies. AAPS Open. 2025;11:5. doi: 10.1186/s41120-025-00108-4 [DOI] [Google Scholar]
- 45.Chaudhury C, Brooks CL, Carter DC, Robinson JM, Anderson CL. Albumin binding to FcRn: distinct from the FcRn-IgG interaction. Biochemistry. 2006;45(15):4983-4990. doi: 10.1021/bi052628y [DOI] [PubMed] [Google Scholar]
- 46.Carvykti (ciltacabtagene autoleucel). Prescribing information. Janssen Biotech; 2025.
- 47.Cablivi (caplacizumab-yhdp). Prescribing information. Ablynx; 2025.
- 48.Cablivi (caplacizumab-yhdp). Summary of product characteristics. Ablynx; 2024.
- 49.Carvykti (ciltacabtagene autoleucel). Summary of product characteristics. Janssen Biotech; 2026.
- 50.Vu T, Habib AA, Jacob S, et al. ; NIMBLE Trial Investigators . Efficacy and safety of cemdisiran siRNA in myasthenia gravis (NIMBLE): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet. 2026;407(10540):1712-1725. doi: 10.1016/S0140-6736(26)00690-2 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial protocol and statistical analysis plan
eAppendix. PREVAIL trial investigators
eMethods
eFigure 1. Key attributes of gefurulimab compared with conventional antibodies
eFigure 2. Trial design
eTable 1. Weight-based dosage regimen of gefurulimab in PREVAIL
eTable 2. Additional baseline patient demographics and clinical characteristics
eTable 3. Concomitant myasthenia gravis therapies used during the randomized controlled treatment period
eTable 4. Treatment-emergent adverse events during the randomized controlled trial period, by worst severity
eTable 5. Serious adverse events considered by the trial investigator to be related to trial agent
eReferences
Data sharing statement
