Complement Inhibitor Gefurulimab Meets End Points in Phase 3 PREVAIL Study of Myasthenia Gravis

Kelly Gwathmey, MD

AstraZeneca has announced positive data from its phase 3 PREVAIL study (NCT05556096), with investigational gefurulimab, a complement C5 inhibitor administered once-weekly, meeting primary and all secondary end points in patients with anti-acetylcholine receptor (AChR) antibody-positive generalized myasthenia gravis (gMG). The company is planning to share more from the study at an upcoming meeting and discuss the findings with global regulatory authorities.¹

PREVAIL, a global, double-blind, placebo-controlled, parallel study, included 260 patients with gMG across 20 countries who were randomly assigned to gefurulimab or placebo for 26 weeks, followed by an optional open-label study. According to the company, treatment with the investigational agent displayed statistically significant and clinically meaningful differences vs placebo on the primary end point of Myasthenia Gravis-Activities of Daily Living (MG-ADL), a common measure for gMG trials.

The trial, which featured only those with anti-AChR antibody-positive gMG, also showed that gefurulimab was safe and well-tolerated, with a profile that matched previous trials of C5 inhibitors. In addition to showing positive effects on the primary outcome, the investigational agent led to statistically significant and clinically meaningful improvements in secondary end points such as Quantitative Myasthenia Gravis total score and Myasthenia Gravis Composite total score.

"Rapidly fluctuating symptoms and the unpredictable disability associated with gMG can affect nearly every aspect of a patient's life, making early intervention and sustained disease control a critical treatment goal,” principal investigator Kelly Gwathmey, MD, associate professor of neurology and chief of Neuromuscular Division at Virginia Commonwealth University, said in a statement. "A once-weekly, self-administered C5 treatment option would offer patients greater convenience and independence in managing their condition, empowering them to have more control over their therapy."

Gefurulimab, a compliment inhibitor, targets and binds to terminal complement protein C5, thereby blocking the terminal complement pathway of complement activation. By binding to albumin via its albumin-binding domain, gefurulimab extends its half-life while inhibiting complement-mediated inflammation and cell lysis—key drivers of tissue destruction in inflammatory and autoimmune diseases such as gMG.

"Building on Alexion’s pioneering leadership in gMG, these positive results from the PREVAIL Phase III trial demonstrate the potential for gefurulimab to offer rapid and sustained disease control for this patient community,” Marc Dunoyer, chief executive officer at Alexion, said in a statement.¹ "These data, reflecting patient participation across 20 countries, reinforce the established safety profile and efficacy of C5 inhibition and show the potential for gefurulimab as a first line biologic, with the convenience of a self-administered option."

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Prior to PREVAIL, gefurulimab was studied in a phase 1 trial of healthy volunteers, primarily to assess pharmacokinetics and safety profile. The trial featured patients aged 18-45 who were randomly assigned 3:1 to either gefurulimab or placebo, for a period of 7 weeks. The data, presented at the 2023 American Academy of Neurology (AAN) annual meeting, showed that the therapy was well tolerated, with no serious adverse events reported.

In the study, patients received either subcutaneous gefurulimab as a single dose (30-1700 mg), multiple doses (100 or 300 mg) once weekly for 3 weeks, or a single dose of intravenous gefurulimab. Overall, serum exposure increased dose dependently over 3 weekly doses of 100 mg and 300 mg, and single doses of at least 100 mg with extended multiple dosing achieved complete terminal complement inhibition (serum free C5 < 0.5 µg/mL). Low-titer, treatment-emergent (TE) anti-drug antibodies were observed in 12% (9/73) of participants who received gefurulimab.

To date, there are 2 FDA-approved complement inhibitors for the treatment of gMG in patients who are anti-AChR antibody-positive. These include eculizumab (Soliris; Alexion), a terminal complement inhibitor approved in 2017 for adults, and ravulizumab (Ultomiris; Alexion), a long-acting C5 complement inhibitor approved in 2022. Both of these therapies work by inhibiting C5 in the complement cascade, reducing immune-mediated destruction; however, ravulizumab has the benefit of less frequent dosing.

REFERENCES
1. Gefurulimab dual-binding nanobody demonstrated statistically significant and clinically meaningful improvement in functional activities of daily living in adults with generalised myasthenia gravis in PREVAIL Phase III trial. News release. AstraZeneca. Published July 24, 2025. Accessed July 24, 2025. https://www.astrazeneca.com/media-centre/press-releases/2025/gefurulimab-nanobody-met-phase-iii-endpoints.html
2. Ortiz S, McEneny A, Amancha P, et al. Safety, tolerability, pharmacokinetics, pharmacodynamics and immunogenicity of subcutaneous and intravenous ALXN1720 in healthy volunteers: a phase 1, randomized, double-blind, placebocontrolled, single and multiple ascending dose study. Presented at: 2023 AAN Annual Meeting. ABSTRACT P1-5.016