PREVAIL
Efficacy and Safety of Gefurulimab in Generalized Myasthenia Gravis: The PREVAIL Phase 3 Randomized Clinical Trial
Year of Publication: 2026
Authors: Gwathmey KG, Saccà F, Howard JF Jr, et al; PREVAIL Trial Investigators
Journal: JAMA Neurology
Citation: JAMA Neurol. 2026 Jul 27:e262333. Online ahead of print. DOI: 10.1001/jamaneurol.2026.2333
PDF: Clinical Question
Does once-weekly subcutaneous gefurulimab, a dual-binding anti-albumin/anti-C5 nanobody, improve MG-ADL score at 26 weeks vs placebo in adults with AChR-Ab+ generalized myasthenia gravis, with acceptable safety?
Study Overview
Objective
Left atrial appendage (LAA) occlusion with the Watchman device versus warfarin in patients with nonvalvular atrial fibrillation (NVAF).
Study Summary
In patients with NVAF at risk for stroke, the Watchman device was noninferior to warfarin for prevention of late ischemic stroke or systemic embolism. However, noninferiority was not met for the overall efficacy composite. Procedural safety significantly improved compared to prior trials.
Intervention
Randomized 2:1 to Watchman device implantation vs. warfarin therapy. Patients had NVAF and CHADS2 ≥2 (or 1 with additional risk factor). Device group discontinued warfarin after successful implantation per protocol. Follow-up: median 12 months.
Bottom Line
In the phase 3 PREVAIL trial of 260 adults with AChR-Ab+ generalized myasthenia gravis, once-weekly subcutaneous gefurulimab significantly reduced MG-ADL at 26 weeks vs placebo (LS mean change −4.2 vs −2.6; treatment difference −1.6, 95% CI −2.4 to −0.8; P<.001), with concordant benefit on QMG (−4.5 vs −2.4; difference −2.1, P<.001) and MGC (−7.8 vs −4.7; difference −3.1, P<.001). Improvements appeared as early as week 1 and were sustained through 26 weeks, with a safety profile similar to placebo and no meningococcal infections. Gefurulimab is an efficacious, self-administered, weekly subcutaneous option for AChR-Ab+ gMG.
Major Points
- Phase 3, randomized, double-blind, placebo-controlled trial at 113 sites in 20 countries; 260 adults with AChR-Ab+ gMG (MGFA II–IV, MG-ADL ≥5) randomized 1:1 to weight-based weekly subcutaneous gefurulimab (n=131) or matching placebo (n=129) for 26 weeks; 249 (95.8%) completed the RCT.
- Primary end point (LS mean change in MG-ADL from baseline to week 26) achieved: −4.2 (95% CI −4.7 to −3.6) vs −2.6 (−3.1 to −2.0); treatment difference −1.6 (95% CI −2.4 to −0.8; P<.001).
- Key secondary QMG change at week 26: −4.5 (−5.2 to −3.8) vs −2.4 (−3.1 to −1.7); difference −2.1 (−3.1 to −1.1; P<.001). MGC change: −7.8 vs −4.7; difference −3.1 (−4.4 to −1.7; P<.001).
- Responder analyses: ≥5-point QMG reduction 46.3% vs 25.2% (OR 2.56, 1.42–4.62; P=.002); ≥3-point MG-ADL reduction 65.5% vs 52.2% (OR 1.74, 1.03–2.93; P=.04).
- Onset of effect was early: MG-ADL separated by week 1 (difference −1.3; 95% CI −1.9 to −0.8; P<.001) and QMG by week 4 (difference −1.8; 95% CI −2.5 to −1.1; P<.001); benefit sustained through week 26.
- Rescue therapy required by 7 patients (5.3%) on gefurulimab vs 16 (12.4%) on placebo.
- Safety: any treatment-emergent AE 75.6% vs 80.6%; serious AEs 9.2% vs 11.6%; trial-related serious AEs 0 vs 2 (Bacillus bacteremia, herpes zoster in placebo); injection-site reactions 9.9% vs 3.1% (mostly mild, first 3 weeks, none led to discontinuation); no meningococcal infections in either arm.
- One death per arm; neither considered related to trial intervention (dengue fever on gefurulimab; metabolic acidosis from multiorgan failure on placebo).
Design
Study Type: Phase 3, randomized, double-blind, placebo-controlled multicenter trial with open-label extension (this report: 26-week RCT period only)
Randomization: 1
Blinding: Double-blind (patients and investigators); matching placebo prefilled syringes; 1:1 allocation stratified by geographical region and baseline body weight (<80 vs ≥80 kg).
Enrollment Period: November 2022 – November 2024
Follow-up Duration: 26-week randomized controlled treatment period (open-label extension up to 202 weeks ongoing)
Centers: 113
Countries: Global — 20 countries across North America, South America, Europe, Japan, China, and rest of Asia-Pacific
Sample Size: 260
Power Calculation: Based on the CHAMPION MG (ravulizumab) result and 10% attrition, 254 patients provided ~90% power at 2-sided α=0.05 to detect a treatment effect on change from baseline in MG-ADL at week 26.
Analysis: All randomized patients who received ≥1 dose analyzed regardless of intercurrent events (rescue therapy, discontinuation). Continuous end points analyzed by mixed-effects model for repeated measures (MMRM) with fixed effects for treatment, stratification factors (region, baseline body weight <80 vs ≥80 kg), baseline score, visit and treatment×visit; missing data not imputed (assumed MAR). Responder end points by generalized linear mixed model. Primary and key secondary tested in fixed-sequence hierarchical procedure at 2-sided α=0.05; if both significant, remaining secondaries tested with Holm-Bonferroni. Sensitivity analyses on missing data and per-protocol set.
Inclusion Criteria
- Adults aged ≥18 years
- Documented diagnosis of generalized myasthenia gravis ≥90 days before screening
- Positive serological test for anti-AChR autoantibodies at screening
- MGFA clinical classification II–IV at screening
- MG-ADL total score ≥5 at screening and on day 1 before randomization
- Meningococcal (N meningitidis) vaccination within 3 years before day 1 (or vaccinated before first dose, with prophylactic antibiotics if <2 weeks pre-dose)
- Continued use of previously prescribed MG therapies (corticosteroids, nonsteroidal immunosuppressants, IVIg/SCIg) permitted if doses stable and well tolerated
Exclusion Criteria
- Prior treatment with a complement or FcRn inhibitor within less than 5 half-lives before day 1
- Inadequate meningococcal vaccination without appropriate mitigation
- Additional protocol-specified medical, laboratory, and safety exclusions (full list in Supplement 1)
Baseline Characteristics
| Characteristic | Gefurulimab (n=131) | Placebo (n=129) |
|---|---|---|
| Age at first dose, mean (SD), y | 53.0 (14.42) | 52.7 (17.00) |
| Female n (%) | 78 (59.5) | 79 (61.2) |
| Male n (%) | 53 (40.5) | 50 (38.8) |
| Race — White n (%) | 69 (52.7) | 74 (57.4) |
| Race — Asian n (%) | 43 (32.8) | 38 (29.5) |
| Race — Black or African American n (%) | 3 (2.3) | 3 (2.3) |
| Region — Europe n (%) | 57 (43.5) | 56 (43.4) |
| Region — North America n (%) | 16 (12.2) | 15 (11.6) |
| Region — China n (%) | 16 (12.2) | 15 (11.6) |
| MGFA class II (IIa/IIb) n (%) | 48 (36.6) | 45 (34.9) |
| MGFA class III (IIIa/IIIb) n (%) | 76 (58.0) | 77 (59.7) |
| MGFA class IV (IVa/IVb) n (%) | 7 (5.4) | 7 (5.4) |
| Baseline MG-ADL total score, mean (SD) | 9.0 (2.29) | 9.0 (2.03) |
| Baseline QMG total score, mean (SD) | 14.9 (4.38) | 14.7 (4.39) |
| Baseline MGC total score, mean (SD) | 16.4 (5.32) | 16.1 (5.39) |
| Age at MG diagnosis, mean (SD), y | 43.8 (17.55) | 44.6 (19.37) |
| Time from MG diagnosis to first dose, mean (SD), y | 9.2 (8.45) | 8.2 (8.79) |
| Receiving corticosteroids at baseline n (%) | 84 (64.1) | 92 (71.3) |
| Receiving nonsteroidal immunosuppressant at baseline n (%) | 79 (60.3) | 72 (55.8) |
Arms
| Field | Gefurulimab | Control |
|---|---|---|
| Intervention | Gefurulimab (dual-binding anti-albumin/anti-C5 nanobody, ALXN1720): weight-based loading dose 600 or 900 mg SC on day 1, then maintenance 300 or 600 mg SC weekly (patient/caregiver self-injection with prefilled syringe) for 26 weeks | Matching placebo SC weekly with prefilled syringe for 26 weeks |
| N | 131 | 129 |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Change from baseline in MG-ADL total score (range 0–24, higher = worse) at week 26; MMRM in the analysis set of all randomized patients receiving ≥1 dose. | Primary | LS mean change −2.6 (95% CI −3.1 to −2.0) | LS mean change −4.2 (95% CI −4.7 to −3.6) | <0.001 | |
| Change from baseline in QMG total score at week 26 (key secondary; range 0–39, higher = worse) | Secondary | LS mean −2.4 (95% CI −3.1 to −1.7) | LS mean −4.5 (95% CI −5.2 to −3.8) | <0.001 | |
| ≥5-point reduction in QMG total score at week 26 (responder) | Secondary | 33/118 (28.0%); adjusted 25.2% | 58/124 (46.8%); adjusted 46.3% | 0.002 | |
| ≥3-point reduction in MG-ADL total score at week 26 (responder) | Secondary | 63/121 (52.1%); adjusted 52.2% | 82/125 (65.6%); adjusted 65.5% | 0.04 | |
| Change from baseline in MGC total score at week 26 (range 0–50, higher = worse) | Secondary | LS mean −4.7 (95% CI −5.7 to −3.8) | LS mean −7.8 (95% CI −8.8 to −6.8) | <0.001 | |
| Change from baseline in QMG total score at week 4 (early onset) | Secondary | LS mean −1.5 (95% CI −2.0 to −1.0) | LS mean −3.3 (95% CI −3.9 to −2.7) | <0.001 | |
| Change from baseline in MG-ADL total score at week 1 (early onset) | Secondary | — | Reported significantly better than placebo | <0.001 | |
| Receipt of rescue therapy during 26-week RCT | Secondary | 16/129 (12.4%) | 7/131 (5.3%) | ||
| Any treatment-emergent AE | Safety | 104/129 (80.6%) | 99/131 (75.6%) | ||
| Any AE related to trial intervention | Safety | 36/129 (27.9%) | 36/131 (27.5%) | ||
| Any serious AE | Safety | 15/129 (11.6%) | 12/131 (9.2%) | ||
| Serious AE related to trial intervention | Safety | 2/129 (1.6%) — Bacillus bacteremia, herpes zoster | 0/131 (0%) | ||
| AE leading to discontinuation of trial intervention | Safety | 1/129 (0.8%) — vitamin D deficiency | 1/131 (0.8%) — suicide attempt | ||
| AE of special interest (meningococcal infection) | Safety | 0/129 (0%) | 0/131 (0%) | ||
| Injection site reactions (combined preferred terms) | Safety | 4/129 (3.1%) | 13/131 (9.9%) | ||
| Grade 3 AE | Safety | 16/129 (12.4%) | 13/131 (9.9%) | ||
| Grade 4 AE | Safety | 5/129 (3.9%) | 3/131 (2.3%) | ||
| Death (Grade 5) | Safety | 1/129 (0.8%) — metabolic acidosis/multiorgan failure, unrelated | 1/131 (0.8%) — dengue fever, unrelated | ||
| Headache | Safety | 16/129 (12.4%) | 13/131 (9.9%) | ||
| Back pain | Safety | 2/129 (1.6%) | 10/131 (7.6%) | ||
| Nasopharyngitis | Safety | 9/129 (7.0%) | 9/131 (6.9%) | ||
| Upper respiratory tract infection | Safety | 10/129 (7.8%) | 8/131 (6.1%) | ||
| Diarrhea | Safety | 11/129 (8.5%) | 8/131 (6.1%) | ||
| Urinary tract infection | Safety | 4/129 (3.1%) | 7/131 (5.3%) | ||
| COVID-19 | Safety | 9/129 (7.0%) | 5/131 (3.8%) | ||
| Dizziness | Safety | 8/129 (6.2%) | 2/131 (1.5%) |
Subgroup Analysis
The paper emphasizes that primary and secondary end points were met with statistical significance across the population; formal prespecified subgroup analyses (by region, weight, MGFA class) are shown in Supplement 2 and are described as consistent with the overall result. No effect-modification interactions were highlighted in the main text.
Criticisms
- Short controlled duration (26 weeks) — long-term efficacy, durability, and rare adverse events (including meningococcal infection risk on any C5 inhibitor) require the ongoing open-label extension.
- No active comparator: benefit is quantified vs placebo only. Cross-trial comparisons to eculizumab, ravulizumab, zilucoplan, efgartigimod, rozanolixizumab, and nipocalimab must be interpreted with caution given differences in populations, endpoints, and mechanisms.
- Underrepresentation of Black or African American patients (2.3%) limits generalizability to this population despite the trial's overall geographic diversity.
- Sponsor (Alexion, AstraZeneca Rare Disease) had a role in trial design, conduct, data management, analysis, and manuscript preparation.
- Small imbalances in baseline features (ocular MG as first presentation, prior thymectomy, immunoglobulin use) between groups, though considered unlikely to affect overall results.
- Rescue therapy allowed but analyzed regardless of intercurrent events; higher rescue use in placebo (12.4% vs 5.3%) could bias against showing an even larger gefurulimab effect.
- Meningococcal infection risk of C5 blockade remains a class concern despite mandatory vaccination and none observed in this 26-week window.
Funding
Sponsored by Alexion, AstraZeneca Rare Disease, which had a role in trial design and conduct; data collection, management, analysis, and interpretation; manuscript preparation, review, and approval; and decision to submit for publication.
Based on: PREVAIL (JAMA Neurology, 2026)
Authors: Gwathmey KG, Saccà F, Howard JF Jr, et al; PREVAIL Trial Investigators
Citation: JAMA Neurol. 2026 Jul 27:e262333. Online ahead of print. DOI: 10.1001/jamaneurol.2026.2333
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