Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE) : a randomised, double-blind, placebo-controlled, phase 3 study
Copyright © 2023 Elsevier Ltd. All rights reserved..
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.
| Errataetall: |
CommentIn: Lancet Neurol. 2023 May;22(5):368-369. - PMID 37059497 |
|---|---|
| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
|---|---|
| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:22 |
|---|---|
| Enthalten in: |
The Lancet. Neurology - 22(2023), 5 vom: 07. Mai, Seite 395-406 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Howard, James F [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
Clinical Trial, Phase III |
|---|
| Anmerkungen: |
Date Completed 18.04.2023 Date Revised 15.03.2024 published: Print ClinicalTrials.gov: NCT04225871, NCT04115293 CommentIn: Lancet Neurol. 2023 May;22(5):368-369. - PMID 37059497 Citation Status MEDLINE |
|---|
| doi: |
10.1016/S1474-4422(23)00080-7 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM355636603 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM355636603 | ||
| 003 | DE-627 | ||
| 005 | 20240315232624.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231226s2023 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/S1474-4422(23)00080-7 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1330.xml |
| 035 | |a (DE-627)NLM355636603 | ||
| 035 | |a (NLM)37059508 | ||
| 035 | |a (PII)S1474-4422(23)00080-7 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Howard, James F |c Jr |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE) |b a randomised, double-blind, placebo-controlled, phase 3 study |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 18.04.2023 | ||
| 500 | |a Date Revised 15.03.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a ClinicalTrials.gov: NCT04225871, NCT04115293 | ||
| 500 | |a CommentIn: Lancet Neurol. 2023 May;22(5):368-369. - PMID 37059497 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier Ltd. All rights reserved. | ||
| 520 | |a 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 | ||
| 520 | |a 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) | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 520 | |a FUNDING: UCB Pharma | ||
| 650 | 4 | |a Randomized Controlled Trial | |
| 650 | 4 | |a Clinical Trial, Phase III | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a zilucoplan |2 NLM | |
| 650 | 7 | |a YG391PK0CC |2 NLM | |
| 650 | 7 | |a Complement C5 |2 NLM | |
| 650 | 7 | |a Immunologic Factors |2 NLM | |
| 700 | 1 | |a Bresch, Saskia |e verfasserin |4 aut | |
| 700 | 1 | |a Genge, Angela |e verfasserin |4 aut | |
| 700 | 1 | |a Hewamadduma, Channa |e verfasserin |4 aut | |
| 700 | 1 | |a Hinton, John |e verfasserin |4 aut | |
| 700 | 1 | |a Hussain, Yessar |e verfasserin |4 aut | |
| 700 | 1 | |a Juntas-Morales, Raul |e verfasserin |4 aut | |
| 700 | 1 | |a Kaminski, Henry J |e verfasserin |4 aut | |
| 700 | 1 | |a Maniaol, Angelina |e verfasserin |4 aut | |
| 700 | 1 | |a Mantegazza, Renato |e verfasserin |4 aut | |
| 700 | 1 | |a Masuda, Masayuki |e verfasserin |4 aut | |
| 700 | 1 | |a Sivakumar, Kumaraswamy |e verfasserin |4 aut | |
| 700 | 1 | |a Śmiłowski, Marek |e verfasserin |4 aut | |
| 700 | 1 | |a Utsugisawa, Kimiaki |e verfasserin |4 aut | |
| 700 | 1 | |a Vu, Tuan |e verfasserin |4 aut | |
| 700 | 1 | |a Weiss, Michael D |e verfasserin |4 aut | |
| 700 | 1 | |a Zajda, Małgorzata |e verfasserin |4 aut | |
| 700 | 1 | |a Boroojerdi, Babak |e verfasserin |4 aut | |
| 700 | 1 | |a Brock, Melissa |e verfasserin |4 aut | |
| 700 | 1 | |a de la Borderie, Guillemette |e verfasserin |4 aut | |
| 700 | 1 | |a Duda, Petra W |e verfasserin |4 aut | |
| 700 | 1 | |a Lowcock, Romana |e verfasserin |4 aut | |
| 700 | 1 | |a Vanderkelen, Mark |e verfasserin |4 aut | |
| 700 | 1 | |a Leite, M Isabel |e verfasserin |4 aut | |
| 700 | 0 | |a RAISE Study Team |e verfasserin |4 aut | |
| 700 | 1 | |a Sembinelli, Dylan |e investigator |4 oth | |
| 700 | 1 | |a Teitelbaum, Jeanne |e investigator |4 oth | |
| 700 | 1 | |a Nicolle, Michael |e investigator |4 oth | |
| 700 | 1 | |a Bernard, Emilien |e investigator |4 oth | |
| 700 | 1 | |a Svahn, Juliette |e investigator |4 oth | |
| 700 | 1 | |a Spinazzi, Marco |e investigator |4 oth | |
| 700 | 1 | |a Stojkovic, Tanya |e investigator |4 oth | |
| 700 | 1 | |a Demeret, Sophie |e investigator |4 oth | |
| 700 | 1 | |a Weiss, Nicolas |e investigator |4 oth | |
| 700 | 1 | |a Le Guennec, Loïc |e investigator |4 oth | |
| 700 | 1 | |a Messai, Sihame |e investigator |4 oth | |
| 700 | 1 | |a Tranchant, Christine |e investigator |4 oth | |
| 700 | 1 | |a Nadaj-Pakleza, Aleksandra |e investigator |4 oth | |
| 700 | 1 | |a Chanson, Jean-Baptiste |e investigator |4 oth | |
| 700 | 1 | |a Suliman, Muhtadi |e investigator |4 oth | |
| 700 | 1 | |a Zaidi, Leila |e investigator |4 oth | |
| 700 | 1 | |a Tard, Celine |e investigator |4 oth | |
| 700 | 1 | |a Lecointe, Peggy |e investigator |4 oth | |
| 700 | 1 | |a Zschüntzsch, Jana |e investigator |4 oth | |
| 700 | 1 | |a Schmidt, Jens |e investigator |4 oth | |
| 700 | 1 | |a Glaubitz, Stefanie |e investigator |4 oth | |
| 700 | 1 | |a Zeng, Rachel |e investigator |4 oth | |
| 700 | 1 | |a Scholl, Matthias |e investigator |4 oth | |
| 700 | 1 | |a Kowarik, Markus |e investigator |4 oth | |
| 700 | 1 | |a Ziemann, Ulf |e investigator |4 oth | |
| 700 | 1 | |a Krumbholz, Markus |e investigator |4 oth | |
| 700 | 1 | |a Martin, Pascal |e investigator |4 oth | |
| 700 | 1 | |a Ruschil, Christoph |e investigator |4 oth | |
| 700 | 1 | |a Dünschede, Jutta |e investigator |4 oth | |
| 700 | 1 | |a Kemmner, Roswitha |e investigator |4 oth | |
| 700 | 1 | |a Rumpel, Natalie |e investigator |4 oth | |
| 700 | 1 | |a Berger, Benjamin |e investigator |4 oth | |
| 700 | 1 | |a Totzeck, Andreas |e investigator |4 oth | |
| 700 | 1 | |a Hagenacker, Tim |e investigator |4 oth | |
| 700 | 1 | |a Stolte, Benjamin |e investigator |4 oth | |
| 700 | 1 | |a Iorio, Raffaele |e investigator |4 oth | |
| 700 | 1 | |a Evoli, Amelia |e investigator |4 oth | |
| 700 | 1 | |a Falso, Silvia |e investigator |4 oth | |
| 700 | 1 | |a Antozzi, Carlo |e investigator |4 oth | |
| 700 | 1 | |a Frangiamore, Rita |e investigator |4 oth | |
| 700 | 1 | |a Vanoli, Fiammetta |e investigator |4 oth | |
| 700 | 1 | |a Rinaldi, Elena |e investigator |4 oth | |
| 700 | 1 | |a Deguchi, Kazushi |e investigator |4 oth | |
| 700 | 1 | |a Minami, Naoya |e investigator |4 oth | |
| 700 | 1 | |a Nagane, Yuriko |e investigator |4 oth | |
| 700 | 1 | |a Suzuki, Yasushi |e investigator |4 oth | |
| 700 | 1 | |a Ishida, Sayaka |e investigator |4 oth | |
| 700 | 1 | |a Suzuki, Shigeaki |e investigator |4 oth | |
| 700 | 1 | |a Nakahara, Jin |e investigator |4 oth | |
| 700 | 1 | |a Nagaoka, Astushi |e investigator |4 oth | |
| 700 | 1 | |a Yoshimura, Shunsuke |e investigator |4 oth | |
| 700 | 1 | |a Konno, Shingo |e investigator |4 oth | |
| 700 | 1 | |a Tsuya, Youko |e investigator |4 oth | |
| 700 | 1 | |a Uzawa, Akiyuki |e investigator |4 oth | |
| 700 | 1 | |a Kubota, Tomoya |e investigator |4 oth | |
| 700 | 1 | |a Takahashi, Masanori |e investigator |4 oth | |
| 700 | 1 | |a Okuno, Tatsusada |e investigator |4 oth | |
| 700 | 1 | |a Murai, Hiroyuki |e investigator |4 oth | |
| 700 | 1 | |a Gilhus, Nils Erik |e investigator |4 oth | |
| 700 | 1 | |a Boldingh, Marion |e investigator |4 oth | |
| 700 | 1 | |a Rønning, Tone Hakvåg |e investigator |4 oth | |
| 700 | 1 | |a Chyrchel-Paszkiewicz, Urszula |e investigator |4 oth | |
| 700 | 1 | |a Kumor, Klaudiusz |e investigator |4 oth | |
| 700 | 1 | |a Zielinski, Tomasz |e investigator |4 oth | |
| 700 | 1 | |a Banaszkiewicz, Krzysztof |e investigator |4 oth | |
| 700 | 1 | |a Błaż, Michał |e investigator |4 oth | |
| 700 | 1 | |a Kłósek, Agata |e investigator |4 oth | |
| 700 | 1 | |a Świderek-Matysiak, Mariola |e investigator |4 oth | |
| 700 | 1 | |a Szczudlik, Andrzej |e investigator |4 oth | |
| 700 | 1 | |a Paśko, Aneta |e investigator |4 oth | |
| 700 | 1 | |a Szczechowski, Lech |e investigator |4 oth | |
| 700 | 1 | |a Banach, Marta |e investigator |4 oth | |
| 700 | 1 | |a Ilkowski, Jan |e investigator |4 oth | |
| 700 | 1 | |a Kapetanovic Garcia, Solange |e investigator |4 oth | |
| 700 | 1 | |a Ortiz Bagan, Patricia |e investigator |4 oth | |
| 700 | 1 | |a Belén Cánovas Segura, Ana |e investigator |4 oth | |
| 700 | 1 | |a Turon Sans, Joana |e investigator |4 oth | |
| 700 | 1 | |a Vidal Fernandez, Nuria |e investigator |4 oth | |
| 700 | 1 | |a Cortes Vicente, Elena |e investigator |4 oth | |
| 700 | 1 | |a Rodrigo Armenteros, Patricia |e investigator |4 oth | |
| 700 | 1 | |a Ashraghi, Mohammad |e investigator |4 oth | |
| 700 | 1 | |a Cavey, Ana |e investigator |4 oth | |
| 700 | 1 | |a Haslam, Liam |e investigator |4 oth | |
| 700 | 1 | |a Emery, Anna |e investigator |4 oth | |
| 700 | 1 | |a Liow, Kore |e investigator |4 oth | |
| 700 | 1 | |a Yegiaian, Sharon |e investigator |4 oth | |
| 700 | 1 | |a Barboi, Alexandru |e investigator |4 oth | |
| 700 | 1 | |a Vazquez, Rosa Maria |e investigator |4 oth | |
| 700 | 1 | |a Lennon, Joshua |e investigator |4 oth | |
| 700 | 1 | |a Pascuzzi, Robert M |e investigator |4 oth | |
| 700 | 1 | |a Bodkin, Cynthia |e investigator |4 oth | |
| 700 | 1 | |a Guingrich, Sandra |e investigator |4 oth | |
| 700 | 1 | |a Comer, Adam |e investigator |4 oth | |
| 700 | 1 | |a Bromberg, Mark |e investigator |4 oth | |
| 700 | 1 | |a Janecki, Teresa |e investigator |4 oth | |
| 700 | 1 | |a Saba, Sami |e investigator |4 oth | |
| 700 | 1 | |a Tellez, Marco |e investigator |4 oth | |
| 700 | 1 | |a Elsheikh, Bakri |e investigator |4 oth | |
| 700 | 1 | |a Freimer, Miriam |e investigator |4 oth | |
| 700 | 1 | |a Heintzman, Sarah |e investigator |4 oth | |
| 773 | 0 | 8 | |i Enthalten in |t The Lancet. Neurology |d 2002 |g 22(2023), 5 vom: 07. Mai, Seite 395-406 |w (DE-627)NLM126098468 |x 1474-4465 |7 nnns |
| 773 | 1 | 8 | |g volume:22 |g year:2023 |g number:5 |g day:07 |g month:05 |g pages:395-406 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/S1474-4422(23)00080-7 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 22 |j 2023 |e 5 |b 07 |c 05 |h 395-406 | ||