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

Howard, James F.; Bresch, Saskia; Genge, Angela; Hewamadduma, Channa; Hinton, John L.; Hussain, Yessar; Juntas-Moralès, 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, M. Louise; Borderie, Guillemette de la; Duda, Petra W.; Lowcock, Romana; Vanderkelen, Mark; Leite, Maria Isabel; Sembinelli, Dylan; Teitelbaum, Jeanne; Nicolle, Michael W.; Bernard, Emilien; Svahn, Juliette; Spinazzi, Marco; Stojkovic, Tanya; Demeret, Sophie; Weiss, Nicolas; Guennec, Loïc Le; Messai, Sihame; Tranchant, Christine; Nadaj‐Pakleza, Aleksandra; Chanson, Jean‐Baptiste; Suliman, Muhtadi; Zaidi, Leila; Tard, Céline; Lecointe, Peggy; Zschüntzsch, Jana; Schmidt, J; Glaubitz, Stefanie; Zeng, Rachel; Scholl, Matthias; Kowarik, Markus C.; 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 Ingeborg; Rønning, Tone Hakvåg; Chyrchel-Paszkiewicz, U.; Kumor, Klaudiusz; Zieliński, Tomasz; Banaszkiewicz, Krzysztof; Błaż, Michał; Kłósek, Agata; Świderek-Matysiak, Mariola; Szczudlik, Andrzej; Paśko, Aneta; Szczechowski, L; Banach, Marta; Ilkowski, Jan; García, Solange Kapetanovic; Bagan, Patricia Ortiz; Segura, Ana Belén Cánovas; Sans, Joana Turon; Fernández, Nuria Vidal; Vicente, Elena Cortés; Armenteros, Patricia Rodrigo; Ashraghi, Mohammad; Cavey, Ana; Haslam, Liam; Emery, Anna; Liow, Kore; Yegiaian, Sharon; Barboi, Alexandru; Vázquez, R.M.; Lennon, Joshua; Pascuzzi, Robert M.; Bodkin, Cynthia; Guingrich, Sandra; Comer, Adam; Bromberg, Mark B.; Janecki, Teresa; Saba, Sami; Tellez, Marco; Elsheikh, Bakri; Freimer, Miriam; Heintzman, Sarah; Govindarajan, Raghav; Guptill, Jeffrey T.; Massey, Janice M.; Juel, Vern C.; González, Natalia; Habib, Ali A; Mozaffar, Tahseen; Korb, Manisha Kak; Goyal, Namita; Machemehl, Hannah; Manousakis, Georgios; Allen, Jeffrey A.; Harper, E. J.; Farmakidis, Constantine; Saavedra, Lilli; Dimachkie, Mazen M.; Pasnoor, Mamatha; Akhter, Salma; Beydoun, Said R.; McIlduff, Courtney; Nye, Joan; Roy, Bhaskar; Sheldon, Bailey Munro; Nowak, Richard J.; Barnes, Benjamin; Rivner, Michael H.; Suresh, Niraja; Shaw, Jessica; Harvey, Brittany; Lam, Lucy; Thomas, Nikki Lynn; Chopra, Manisha; Traub, Rebecca; 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; 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

doi:10.1016/s1474-4422(23)00080-7

Cited by 72 publications

(62 citation statements)

References 36 publications

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“…RA is a highly heterogeneous autoimmune disease characterized by infiltration of synoviocytes and bone erosion in the local joint cavity [ 40 ]. The drugs (methotrexate, prednisone and dexamethasone) currently used clinically for the treatment of RA have serious side effects, which greatly limit the use of relevant drugs [ 41 , 42 ]. As scientific research has progressed, curcumin has been used to treat RA as a natural product with superior anti-inflammatory and antioxidant activity [ 43 ].…”

Section: Discussionmentioning

confidence: 99%

Chondroitin sulfate-modified tragacanth gum–gelatin composite nanocapsules loaded with curcumin nanocrystals for the treatment of arthritis

Sun,

Du,

Liu

et al. 2024

J Nanobiotechnol

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Rheumatoid arthritis (RA) is a chronic autoimmune disease of yet undetermined etiology that is accompanied by significant oxidative stress, inflammatory responses, and damage to joint tissues. In this study, we designed chondroitin sulfate (CS)-modified tragacanth gum–gelatin composite nanocapsules (CS-Cur-TGNCs) loaded with curcumin nanocrystals (Cur-NCs), which rely on the ability of CS to target CD44 to accumulate drugs in inflamed joints. Cur was encapsulated in the form of nanocrystals into tragacanth gum–gelatin composite nanocapsules (TGNCs) by using an inborn microcrystallization method, which produced CS-Cur-TGNCs with a particle size of approximately 80 ± 11.54 nm and a drug loading capacity of 54.18 ± 5.17%. In an in vitro drug release assay, CS-Cur-TGNCs showed MMP-2-responsive properties. During the treatment of RA, CS-Cur-TGNCs significantly inhibited oxidative stress, promoted the polarization of M2-type macrophages to M1-type macrophages, and decreased the expression of inflammatory factors (TNF-α, IL-1β, and IL-6). In addition, it also exerted excellent anti-inflammatory effects, and significantly alleviated the swelling of joints during the treatment of gouty arthritis (GA). Therefore, CS-Cur-TGNCs, as a novel drug delivery system, could lead to new ideas for clinical therapeutic regimens for RA and GA. Graphical Abstract

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Section: Discussionmentioning

confidence: 99%

Chondroitin sulfate-modified tragacanth gum–gelatin composite nanocapsules loaded with curcumin nanocrystals for the treatment of arthritis

Sun,

Du,

Liu

et al. 2024

J Nanobiotechnol

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“…In this regard, zilcoplan, a subcutaneously self‐administered macrocyclic peptide inhibitor of C5, is expected to have stable and sustained effects for AChR+ gMG patients. 26 …”

Section: Discussionmentioning

confidence: 99%

Real‐world experience with eculizumab and switching to ravulizumab for generalized myasthenia gravis

Tokuyasu,

Suzuki,

Uzawa

et al. 2024

Ann Clin Transl Neurol

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ObjectiveEculizumab and ravulizumab are complement protein C5 inhibitors, showing efficacy and tolerability for patients with anti‐acetylcholine receptor‐positive (AChR+) generalized myasthenia gravis (gMG) in phase 3 clinical trials and subsequent analyses. The purpose of the present study was to evaluate the clinical significance of eculizumab and switching to ravulizumab for refractory AChR+ gMG patients in the real‐world experience.MethodsAmong the database of Japan MG registry survey 2021, we studied AChR+ gMG patients who received eculizumab. We also evaluated these patients who switched from eculizumab to ravulizumab. Responder was defined as an improvement of at least 3 points in MG‐ADL. We performed a questionnaire of preference between eculizumab and ravulizumab.ResultsAmong 1,106 patients with AChR+ gMG, 36 patients (3%) received eculizumab (female 78%, mean age 56.0 years). Eculizumab was preferentially used in severe and refractory MG patients. The duration of eculizumab treatment was 35 months on average. MG‐ADL improved from 9.4 ± 4.9 to 5.9 ± 5.1, and 25 (70%) of the 36 gMG patients were responders. Postintervention status was markedly improved after the eculizumab treatment. Of 13 patients who did not continue eculizumab, 6 showed insufficiencies. Early onset MG was most effective. However, 15 patients switching from eculizumab to ravulizumab kept favorable response and tolerability. Questionnaire surveys showed preference for ravulizumab over eculizumab.InterpretationEculizumab and switching to ravulizumab showed to be effective for refractory AChR+ gMG patients in clinical settings.

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“…Zilucoplan, on the other hand, is a first-in-class synthetic, macrocyclic peptide, which reduces the activation of the complement classical, alternative, or lectin pathways by blocking the generation of activated C5a and C5b from C5. It was authorized for use in generalized myasthenia gravis (Howard et al, 2023). The third C5 inhibitor, avacincaptad pegol, is a pegylated RNA aptamer, that also blocks the activation of complement C5.…”

Section: Other Noteworthy Approvalsmentioning

confidence: 99%

Novel drugs approved by the EMA, the FDA, and the MHRA in 2023: A year in review

Papapetropoulos,

Topouzis,

Alexander

et al. 2024

British J Pharmacology

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In 2023, seventy novel drugs received market authorization for the first time in either Europe (by the EMA and the MHRA) or in the United States (by the FDA). Confirming a steady recent trend, more than half of these drugs target rare diseases or intractable forms of cancer. Thirty drugs are categorized as “first‐in‐class” (FIC), illustrating the quality of research and innovation that drives new chemical entity discovery and development. We succinctly describe the mechanism of action of most of these FIC drugs and discuss the therapeutic areas covered, as well as the chemical category to which these drugs belong. The 2023 novel drug list also demonstrates an unabated emphasis on polypeptides (recombinant proteins and antibodies), Advanced Therapy Medicinal Products (gene and cell therapies) and RNA therapeutics, including the first‐ever approval of a CRISPR‐Cas9‐based gene‐editing cell therapy.

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

Cited by 72 publications

References 36 publications

Chondroitin sulfate-modified tragacanth gum–gelatin composite nanocapsules loaded with curcumin nanocrystals for the treatment of arthritis

Chondroitin sulfate-modified tragacanth gum–gelatin composite nanocapsules loaded with curcumin nanocrystals for the treatment of arthritis

Real‐world experience with eculizumab and switching to ravulizumab for generalized myasthenia gravis

Novel drugs approved by the EMA, the FDA, and the MHRA in 2023: A year in review

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