Long-term safety and efficacy of zilucoplan in patients with generalized myasthenia gravis: interim analysis of the RAISE-XT open-label extension study

James F Howard Jr; Saskia Bresch; Constantine Farmakidis; Miriam Freimer; Angela Genge; Channa Hewamadduma; John Hinton; Yessar Hussain; Raul Juntas-Morales; Henry J Kaminski; Angelina Maniaol; Renato Mantegazza; Masayuki Masuda; Richard J Nowak; Kumaraswamy Sivakumar; Marek Śmiłowski; Kimiaki Utsugisawa; Tuan Vu; Michael D Weiss; Małgorzata Zajda; Jos Bloemers; Babak Boroojerdi; Melissa Brock; Guillemette de la Borderie; Petra W Duda; Mark Vanderkelen; M Isabel Leite; RAISE-XT Study Team*

doi:10.1177/17562864241243186

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 Apr 17:17:17562864241243186. doi: 10.1177/17562864241243186. eCollection 2024.

Authors

James F Howard Jr¹, Saskia Bresch², Constantine Farmakidis³, Miriam Freimer⁴, Angela Genge⁵, Channa Hewamadduma^{6

7}, John Hinton⁸, Yessar Hussain⁹, Raul Juntas-Morales¹⁰, Henry J Kaminski¹¹, Angelina Maniaol¹², Renato Mantegazza¹³, Masayuki Masuda¹⁴, Richard J Nowak¹⁵, Kumaraswamy Sivakumar¹⁶, Marek Śmiłowski¹⁷, Kimiaki Utsugisawa¹⁸, Tuan Vu¹⁹, Michael D Weiss²⁰, Małgorzata Zajda²¹, Jos Bloemers²², Babak Boroojerdi²³, Melissa Brock²⁴, Guillemette de la Borderie²², Petra W Duda²⁵, Mark Vanderkelen²⁶, M Isabel Leite²⁷; RAISE-XT Study Team*

Affiliations

¹ Department of Neurology, UNC School of Medicine, The University College of North Carolina at Chapel Hill, 2200 Houpt Building, CB#7025, 170 Manning Drive, Chapel Hill, NC 27599-7025, USA.
² Service de Neurologie, Hospital Pasteur, Centre Hospitalier Universitaire de Nice, Nice, France.
³ Neuromuscular Division, Department of Neurology, University of Kansas Medical Center, Kansas City, KS, USA.
⁴ Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
⁵ Clinical Research Unit, Montreal Neurological Institute, Montreal, QC, Canada.
⁶ Academic Neuroscience Unit, Sheffield Teaching Hospitals Foundation Trust, Sheffield, UK.
⁷ Sheffield Institute for Translational Neurosciences (SITRAN), University of Sheffield, Sheffield, UK.
⁸ Department of Neurology, Frederick P. Whiddon School of Medicine, University of South Alabama, Mobile, AL, USA.
⁹ Department of Neurology, Dell Medical School, The University of Texas at Austin, Austin, TX, USA.
¹⁰ Department of Neurology, Vall d'Hebron University Hospital, Barcelona, Spain.
¹¹ Department of Neurology and Rehabilitation Medicine, George Washington University, Washington, DC, USA.
¹² Department of Neurology, Oslo University Hospital, Oslo, Norway.
¹³ Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Neurologico Carlo Besta, Milan, Italy.
¹⁴ Department of Neurology, Tokyo Medical University, Tokyo, Japan.
¹⁵ Department of Neurology, Yale School of Medicine, New Haven, CT, USA.
¹⁶ Neuromuscular Clinic and Research Center, Phoenix, AZ, USA.
¹⁷ Department of Hematology and Bone Marrow Transplantation, Medical University of Silesia, Katowice, Poland.
¹⁸ Department of Neurology, Hanamaki General Hospital, Hanamaki, Japan.
¹⁹ Department of Neurology, University of South Florida Morsani College of Medicine, Tampa, FL, USA.
²⁰ Department of Neurology, University of Washington Medical Center, Seattle, WA, USA.
²¹ Department of Experimental and Clinical Pharmacology, Medical University of Warsaw, Warsaw, Poland.
²² UCB Pharma, Brussels, Belgium.
²³ UCB Pharma, Monheim am Rhein, Germany.
²⁴ UCB Pharma, Raleigh, NC, USA.
²⁵ UCB Pharma, Cambridge, MA, USA.
²⁶ UCB Pharma, Braine-L'Alleud, Belgium.
²⁷ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.

Abstract

Background: Generalized myasthenia gravis (gMG) is a chronic, unpredictable disease associated with high treatment and disease burdens, with a need for more effective and well-tolerated treatments.

Objectives: To evaluate the long-term safety, tolerability, and efficacy of zilucoplan in a mild-to-severe, acetylcholine receptor autoantibody-positive (AChR+) gMG population.

Design: Ongoing, multicenter, phase III open-label extension (OLE) study.

Methods: Eligible patients had completed a qualifying randomized, placebo-controlled phase II or phase III zilucoplan study and received daily, self-administered subcutaneous 0.3 mg/kg zilucoplan. The primary endpoint was incidence of treatment-emergent adverse events (TEAEs). Secondary efficacy endpoints included change from baseline in Myasthenia Gravis Activities of Daily Living (MG-ADL) score.

Results: In total, 200 patients enrolled. At the cut-off date (8 September 2022), median (range) exposure to zilucoplan in RAISE-XT was 1.2 (0.11-4.45) years. Mean age at OLE baseline was 53.3 years. A total of 188 (94%) patients experienced a TEAE, with the most common being MG worsening (n = 52, 26%) and COVID-19 (n = 49, 25%). In patients who received zilucoplan 0.3 mg/kg in the parent study, further improvements in MG-ADL score continued through to Week 24 (least squares mean change [95% confidence interval] from double-blind baseline -6.06 [-7.09, -5.03]) and were sustained through to Week 60 (-6.04 [-7.21, -4.87]). In patients who switched from placebo in the parent study, rapid improvements in MG-ADL score were observed at the first week after switching to zilucoplan; further improvements were observed at Week 24, 12 weeks after switching (-6.46 [-8.19, -4.72]), and were sustained through to Week 60 (-6.51 [-8.37, -4.65]). Consistent results were observed in other efficacy endpoints.

Conclusion: Zilucoplan demonstrated a favorable long-term safety profile, good tolerability, and sustained efficacy through to Week 60 with consistent benefits in a broad AChR+ gMG population. Additional long-term data will be available in future analyses.

Trial registration: ClinicalTrials.gov identifier: NCT04225871 (https://clinicaltrials.gov/ct2/show/NCT04225871).

Keywords: C5 inhibitor; clinical trial; myasthenia gravis; open-label extension; zilucoplan.

Associated data

ClinicalTrials.gov/NCT04225871