Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): a randomised, double-blind, placebo-controlled, phase 3 study. Issue 5 (May 2023)

• Record Type: Journal Article
• Authors: Howard, James F; Bresch, Saskia; Genge, Angela; Hewamadduma, Channa; Hinton, John; Hussain, Yessar; Juntas-Morales, Raul; Kaminski, Henry J; Maniaol, Angelina; Mantegazza, Renato; Masuda, Masayuki; Sivakumar, Kumaraswamy; Śmiłowski, Marek; Utsugisawa, Kimiaki; Vu, Tuan; Weiss, Michael D; Zajda, Małgorzata; Boroojerdi, Babak; Brock, Melissa; de la Borderie, Guillemette; Duda, Petra W; Lowcock, Romana; Vanderkelen, Mark; Leite, M Isabel; Sembinelli, Dylan; Teitelbaum, Jeanne; Nicolle, Michael; Bernard, Emilien; Svahn, Juliette; Spinazzi, Marco; Stojkovic, Tanya; Demeret, Sophie; Weiss, Nicolas; Le Guennec, Loïc; Messai, Sihame; Tranchant, Christine; Nadaj-Pakleza, Aleksandra; Chanson, Jean-Baptiste; Suliman, Muhtadi; Zaidi, Leila; Tard, Celine; Lecointe, Peggy; Zschüntzsch, Jana; Schmidt, Jens; Glaubitz, Stefanie; Zeng, Rachel; Scholl, Matthias; Kowarik, Markus; Ziemann, Ulf; Krumbholz, Markus; Martin, Pascal; Ruschil, Christoph; Dünschede, Jutta; Kemmner, Roswitha; Rumpel, Natalie; Berger, Benjamin; Totzeck, Andreas; Hagenacker, Tim; Stolte, Benjamin; Iorio, Raffaele; Evoli, Amelia; Falso, Silvia; Antozzi, Carlo; Frangiamore, Rita; Vanoli, Fiammetta; Rinaldi, Elena; Deguchi, Kazushi; Minami, Naoya; Nagane, Yuriko; Suzuki, Yasushi; Ishida, Sayaka; Suzuki, Shigeaki; Nakahara, Jin; Nagaoka, Astushi; Yoshimura, Shunsuke; Konno, Shingo; Tsuya, Youko; Uzawa, Akiyuki; Kubota, Tomoya; Takahashi, Masanori; Okuno, Tatsusada; Murai, Hiroyuki; Gilhus, Nils Erik; Boldingh, Marion; Rønning, Tone Hakvåg; Chyrchel-Paszkiewicz, Urszula; Kumor, Klaudiusz; Zielinski, Tomasz; Banaszkiewicz, Krzysztof; Błaż, Michał; Kłósek, Agata; Świderek-Matysiak, Mariola; Szczudlik, Andrzej; Paśko, Aneta; Szczechowski, Lech; Banach, Marta; Ilkowski, Jan; Kapetanovic Garcia, Solange; Ortiz Bagan, Patricia; Belén Cánovas Segura, Ana; Turon Sans, Joana; Vidal Fernandez, Nuria; Cortes Vicente, Elena; Rodrigo Armenteros, Patricia; Ashraghi, Mohammad; Cavey, Ana; Haslam, Liam; Emery, Anna; Liow, Kore; Yegiaian, Sharon; Barboi, Alexandru; Vazquez, Rosa Maria; Lennon, Joshua; Pascuzzi, Robert M; Bodkin, Cynthia; Guingrich, Sandra; Comer, Adam; Bromberg, Mark; Janecki, Teresa; Saba, Sami; Tellez, Marco; Elsheikh, Bakri; Freimer, Miriam; Heintzman, Sarah; Govindarajan, Raghav; Guptill, Jeffrey; Massey, Janice M; Juel, Vern; Gonzalez, Natalia; Habib, Ali A; Mozaffar, Tahseen; Korb, Manisha; Goyal, Namita; Machemehl, Hannah; Manousakis, Georgios; Allen, Jeffrey; Harper, Emily; Farmakidis, Constantine; Saavedra, Lilli; Dimachkie, Mazen; Pasnoor, Mamatha; Akhter, Salma; Beydoun, Said; McIlduff, Courtney; Nye, Joan; Roy, Bhaskar; Munro Sheldon, Bailey; Nowak, Richard; Barnes, Benjamin; Rivner, Michael; Suresh, Niraja; Shaw, Jessica; Harvey, Brittany; Lam, Lucy; Thomas, Nikki; Chopra, Manisha; Traub, Rebecca E; Jones, Sarah; Wagoner, Mary; Smajic, Sejla; Aly, Radwa; Katz, Jonathan; Chen, Henry; Miller, Robert G; Jenkins, Liberty; Khan, Shaida; Khatri, Bhupendra; Sershon, Lisa; Pavlakis, Pantelis; Holzberg, Shara; Li, Yuebing; Caristo, Irys B; Marquardt, Robert; Hastings, Debbie; Rube, Jacob; Lisak, Robert P; Choudhury, Aparna; Ruzhansky, Katherine; Sachdev, Amit; Shin, Susan; Bratton, Joan; Fetter, Mary; McKinnon, Naya; McKinnon, Jonathan; Sissons-Ross, Laura; Sahu, Amos; Distad, B Jane;
• Is Part Of: Lancet neurology. Volume 22:Issue 5(2023)
• Page Start: 395
• Page End: 406
• Publication Date: 2023-05
• Subjects: Neurology -- Periodicals; Neurology -- Periodicals; Nervous System Diseases -- Periodicals; Neurologie -- Périodiques; Neurology; Electronic journals; Periodicals; 616.805
• DOI: 10.1016/S1474-4422(23)00080-7
• Languages: English
• ISSNs: 1474-4422

Abstract

Summary: Background: Generalised myasthenia gravis is a chronic, unpredictable, and debilitating rare disease, often accompanied by high treatment burden and with an unmet need for more efficacious and well tolerated treatments. Zilucoplan is a subcutaneous, self-administered macrocyclic peptide complement C5 inhibitor. We aimed to assess safety, efficacy, and tolerability of zilucoplan in patients with acetylcholine receptor autoantibody (AChR)-positive generalised myasthenia gravis. Methods: RAISE was a randomised, double-blind, placebo-controlled, phase 3 trial that was done at 75 sites in Europe, Japan, and North America. We enrolled patients (aged 18–74 years) with AChR-positive generalised myasthenia gravis (Myasthenia Gravis Foundation of America disease class II–IV), a myasthenia gravis activities of daily living (MG-ADL) score of least 6, and a quantitative myasthenia gravis score of at least 12. Participants were randomly assigned (1:1) to receive subcutaneous zilucoplan 0·3 mg/kg once daily by self-injection, or matched placebo, for 12 weeks. The primary efficacy endpoint was change from baseline to week 12 in MG-ADL score in the modified intention-to-treat population (all randomly assigned patients who received at least one dose of study drug and had at least one post-dosing MG-ADL score). Safety was mainly assessed by the incidence of treatment-emergent adverse events (TEAEs) in all patients who had received at least one dose of zilucoplan or placebo. This trial is registered at ClinicalTrials.gov, NCT04115293 . An open-label extension study is ongoing (NCT04225871 ). Findings: Between Sept 17, 2019, and Sept 10, 2021, 239 patients were screened for the study, of whom 174 (73%) were eligible. 86 (49%) patients were randomly assigned to zilucoplan 0·3 mg/kg and 88 (51%) were assigned to placebo. Patients assigned to zilucoplan showed a greater reduction in MG-ADL score from baseline to week 12, compared with those assigned to placebo (least squares mean change −4·39 [95% CI –5·28 to –3·50] vs −2·30 [–3·17 to –1·43]; least squares mean difference −2·09 [−3·24 to −0·95]; p=0·0004). TEAEs occurred in 66 (77%) patients in the zilucoplan group and in 62 (70%) patients in the placebo group. The most common TEAE was injection-site bruising (n=14 [16%] in the zilucoplan group and n=8 [9%] in the placebo group). Incidences of serious TEAEs and serious infections were similar in both groups. One patient died in each group; neither death (COVID-19 [zilucoplan] and cerebral haemorrhage [placebo]) was considered related to the study drug. Interpretation: Zilucoplan treatment showed rapid and clinically meaningful improvements in myasthenia gravis-specific efficacy outcomes, had a favourable safety profile, and was well tolerated, with no major safety findings. Zilucoplan is a new potential treatment option for a broad population of patients with AChR-positive generalised myasthenia gravis. The long-term safety and efficacy of zilucoplan is being assessed in an ongoing open-label extension study. Funding: UCB Pharma.