A Phase 3, Open-Label, Multicenter Study To Evaluate Eculizumab In Adolescents With Refractory Generalized Myasthenia Gravis
John F. Brandsema1, Matthew Ginsberg2, Hideki Hoshino3, Masakazu Mimaki3, Satoru Nagata4, Vamshi Rao5, Katherine Ruzhansky6, Niraja Suresh7, Emmanuelle Tiongson8, Hideo Yamanouchi9, Glen Frick10, Eden Hicks10, Serena Liao10, James Howard11
1Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA, 2Department of Neurology, Akron Children’s Hospital, Akron, OH, USA, 3Department of Pediatrics, Teikyo University School of Medicine, Tokyo, Japan, 4Department of Pediatrics, Tokyo Women’s Medical University School of Medicine, Tokyo, Japan, 5Division of Neurology, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA, 6Department of Neurology, Medical University of South Carolina, Charleston, SC, USA, 7University of South Florida Department of Neurology, University of South Florida, Tampa, FL, USA, 8Division of Neurology, Children’s Hospital Los Angeles, Los Angeles, CA, USA, 9Department of Pediatrics, Saitama Medical University, Saitama, Japan, 10Alexion, AstraZeneca Rare Disease, Boston, MA, USA, 11Department of Neurology, The University of North Carolina, Chapel Hill, NC, USA
Objective:
To evaluate eculizumab for the treatment of adolescents with refractory anti-acetylcholine receptor antibody-positive (AChR Ab+) generalized myasthenia gravis (gMG).
Background:
Patients with AChR Ab+ gMG have uncontrolled complement activation leading to neuromuscular junction destruction and impaired neuromuscular transmission, resulting in debilitating fatigable muscle weakness. In addition to established treatment, there remains a need for targeted therapies for MG. Eculizumab, a terminal complement C5 inhibitor, has demonstrated safety and efficacy in adults with refractory AChR Ab+ gMG.
Design/Methods:
A phase 3, open-label, multicenter study was conducted in adolescents 12–17 years (NCT03759366). Eculizumab was administered using a weight-based dosing regimen, with weekly induction (1–2 doses of 600 mg or 4 doses of 900 mg) followed by 2-weekly maintenance (300–1200 mg). The primary endpoint was change from baseline to week 26 in Quantitative Myasthenia Gravis (QMG) total score. Multiple secondary endpoints were assessed, including change from baseline to week 26 in MG-Activities of Daily Living (MG-ADL) total score. Pharmacodynamics and safety were also assessed.
Results:
Eleven adolescents (mean age 14.8±1.8 years) were enrolled, of whom six were receiving chronic intravenous immunoglobulin (IVIg). Ten patients completed the primary evaluation period. Least-square mean changes from baseline at week 26 were -5.8 (standard error [SE] 1.2; p=0.0004) for QMG total score and -2.3 (SE 0.6; p=0.0017) for MG-ADL total score. Similar changes were observed irrespective of chronic IVIg treatment. Overall, the primary and all secondary efficacy endpoint analyses met statistical significance at week 1. Improvements were sustained through week 26. Complete terminal complement inhibition was sustained throughout 26 weeks in all patients. Treatment-emergent adverse events were all mild/moderate and predominantly unrelated to eculizumab. Three patients experienced six serious adverse events (MG worsening [3], MG crisis, peritonsillar abscess, pyrexia). No meningococcal infections were reported.
Conclusions:
Eculizumab was efficacious and well-tolerated in adolescents with refractory AChR Ab+ gMG.