Phase 3 PREVAIL Study to Test Bispecific Nanoantibody Gefurulimab in Generalized Myasthenia Gravis

Tuan Vu, MD

Gefurulimab (Alexion), a new bispecific nanoantibody that binds to complement component 5 (C5), is currently being tested in a phase 3, multicenter study, dubbed PREVAIL (NCT05556096), that will assess its efficacy and safety among patients with generalized myasthenia gravis (gMG). The study is currently active and recruiting patients at nearly 160 sites across North America, South America, Europe, Asia, and the Pacific region.¹

Upon administration, gefurulimab, with its anti-C5 antibody moiety, targets and binds to terminal complement protein C5, therby blocking the terminal complement pathway of complement activation. This inhibits complement-mediated inflammation and cell lysis. Excessive complement activation plays a role in various inflammatory and autoimmune diseases like gMG, and leads to destruction. The binding of gefurulimab to albumin, with its albumin binding domain, increases its half-life.²

The design of PREVAIL was presented at the 2024 American Association of Neuromuscular & Electrodiagnostic Medicine (AANEM) meeting, held October 15-18, in Savannah, Georgia, by senior author Tuan Vu, MD, division director of Neuromuscular Medicine & EMG at USF Health. Overall, the study will enroll no more than 254 adults with anti-acetylcholine receptor antibody-positive (AChR-Ab+) gMG who will be randomly assigned 1:1 to either weekly subcutaneous self-injection of gefurulimab or placebo. Investigators will primarily assess the drug’s effect on Myasthenia Gravis Activities of Daily Living (MG-ADL) total score, a traditional end point for MG studies.

The study, which is expected to complete in 2027, also includes a few secondary end points, such as change in Quantitative Myasthenia Gravis total score and Myasthenia Gravis Composite total score. PREVAIL will also include measures of safety, pharmacokinetics, pharmacodynamics, immunogenicity, and quality of life. In the study, patients will be followed for a 26-week double-blind period, with an optional open-label extension for those who complete the study.

READ MORE: Concomitant Corticosteroid Use Decreased in Myasthenia Gravis Through Ravulizumab

In terms of criteria to meet to enter the study, only those with a diagnosis of MG with generalized muscle weakness meeting the clinical criteria defined by Myasthenia Gravis Foundation of America Class II, III, or IV will be included. In addition, patients must provide a positive serological test for autoantibodies against AChR. Those with a history of thymectomy, Neisseria meningitidis infection, or are pregnant, breastfeeding, or intent to conceive during the study will be excluded. In addition, those with untreated thymic malignancy, carcinoma, or thymoma, will also be excluded.

Last year, at the 2023 American Academy of Neurology (AAN) annual meeting, investigators presented findings from a phase 1 study of healthy volunteers assessing the pharmacokinetics and safety of gefurulimab delivered via autoinjector. In the study, healthy volunteers aged 18-45 years were recruited into 12 cohorts at a single site in the UK. IN each cohort, participants were randomly assigned 3:1 to receive gefurulimab or placebo.³

In the study, patients received either subcutaneous gefurulimab, also known as ALXN1720, as a single dose (30–1700 mg), multiple doses (100 or 300 mg) once weekly for three weeks, or a single dose of IV ALXN1720 (300 mg). One cohort received SC 900 mg loading dose then 600 mg maintenance doses once weekly for seven weeks. All told, the therapy was well tolerated with no serious adverse events reported. All told, serum exposure increased dose dependently over 3 weekly doses of 100 mg and 300 mg. Single doses of at least 100 mg and extended multiple dosing achieved complete terminal complement inhibition (serum free C5 < 0.5 ug/mL). Low-titer, treatment-emergent (TE)-anti-drug antibodies were observed in 12% (9/73) of participants who received gefurulimab.

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REFERENCES
1. Howard JF, Gwathmey KG, Zhao C, et al. The phase 3 PREVAIL study assessing the efficacy and safety of subcutaneous gefurulimab in adults with generalized myasthenia gravis: trial in progress. Presented at: 2024 AANEM Annual Meeting; October 15-18; Savannah, GA.
2. Gefurulimab. National Cancer Institute. https://www.cancer.gov/publications/dictionaries/cancer-drug/def/gefurulimab. Accessed October 16, 2024.
3. 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