Objectives Recent advances in systemic sclerosis (SSc) show that it involves a T-helper type-2-oriented immune response with interleukin (IL)-4 and IL-13. Romilkimab is an engineered, humanised, bispecific immunoglobulin-G4 antibody that binds and neutralises IL-4/IL-13 making it ideal for exploration in fibrosis.
Methods Patients aged ≥18 years diagnosed with diffuse cutaneous SSc (dcSSc), and with or without immunosuppressive background therapy, were randomised (1:1) to subcutaneous romilkimab 200 mg or placebo one time per week for 24 weeks in this double-blind, proof-of-concept, phase II study. The primary endpoint was change in modified Rodnan skin score (mRSS) from baseline to week 24.
Results Ninety-seven patients were randomised to romilkimab (n=48) or placebo (n=49) for 24 weeks. Least-squares mean (SE) change in mRSS was –4.76 (0.86) for romilkimab versus –2.45 (0.85) for placebo yielding a mean (SE) (90% CI) difference of –2.31 (1.21) (–4.32 to –0.31; p=0.0291, one-sided). Treatment-emergent AEs were balanced between placebo (n=41; 84%) and romilkimab (n=40; 80%). Most were mild-to-moderate and discontinuations were low (three overall). There were two deaths (one scleroderma renal crisis (romilkimab) and one cardiomyopathy (placebo)), neither were considered treatment related. Two patients in the placebo group had a cardiovascular treatment-emergent SAE (one cardiac failure, one cardiomyopathy), but there were no cardiac safety signals with romilkimab.
Conclusion This study demonstrated significant effects on skin changes with romilkimab in early dcSSc that require confirmation with a longer and more comprehensive phase III study to determine clinical relevance.
Trial registration number NCT02921971.
- autoimmune diseases
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YA and PW are joint first authors.
Handling editor Josef S Smolen
Collaborators Yannick Allanore, Hugo Ascencio, Shervin Assassi, Hilario Avila Armengol, Jerome Avouac, Andra Balanescu, Guillermo Gerardo Bartel, Doreen Belz, Lorenzo Beretta, Horacio Berman, Francesco Boin, Mihai Bojinca, Violeta Bojinca, Martin Brom, Justyna Cal-Kocikowska, Maria Gabriela Cardozo, Renato Carignola, Emmanuel Chatelus, Soumya Chatterjee, Dorota Cieslak, Maurizio Cutolo, Maria Dall’Era, Behrus Darvishan, Ellen De Langhe, Nicoletta Del Papa, Christopher Denton, Oxana Desinova, Villafañe Nicolas Javier Destefani, Katrin Elsharkawi-Welt, Jorge A Esquivel-Valerio, Gulshat Fatkhullina, Dmytro Fedkov, Eugen Feist, Renaud Felten, Rosanna Ferreira Lopez, Alvarado Diana Elsa Flores, Rene A Flores-Franco, Ignacio Garcia-De La Torre, Maria Victoria Garcia, Ignacio Garcia Valladares, Olena Garmisch, Ana Gheorghiu, Andrey Gnilorybov, Bello Yelitza Concepción González, Maria Groseanu, Walter Hermann, Pawel Hrycaj, Oleg Iaremenko, Janusz Jaworski, Christian Jorgensen, Rimma Kamalova, Alina Kamynina, Claudia Kedor, Natalie Kelp, Elsa Khazeeva, Piotr Klepacki, Aleksandra Kolczewska, Ramona König, Volodymyr Kovalenko, Thomas Krieg, Marina Letaeva, Pavlo Logoida, Natalia Loschits, Lukasz Lubinski, Wanda Maglione, Olga Malyshenko, Elena-Laura Margarint, Ciprian M Marinescu, Alejandro Martelli, Maureen Mayes, Diana Mazilu, Valeriia Melokhina, Karin Melsens, Christopher Meneses Lopez, Maria Mirza, Maria Misterska-Skora, Pia Moinzadeh, Erika Montabone, Ulf Müller-Ladner, Edgardo Munoz-Esteves, Ene Ojassalu, Daniela Opris, Cesar Tena Pacheco, Hugo Parra Ruiz, Lorena Perez Barbosa, Yves-Marie Pers, Ana Petcu, Liubov Petelytska, Christiane Pfeiffer, Yves Piette, Oksana Pirogova, Horatiu V Popoviciu, Kaitlin Quinn, Tatiana Raskina, Eve-Kai Raussi, Simona Rednic, Greta Reyes, Janett Riega, Roberto Jesus Gallegos Rivero, Mariano Rivero, Andrii Romanovskyi, Ewa Rzeszewska, Mirtha Sabelli, Mikhail Sandin, Maria Lida Santiago, Mikk Saretok, Ioana Saulescu, Lena Schriever, Agata Sebastian, Adriana Severino, Anca Sindrilaru, Cassandra Skinner, Vanessa Smith, Christelle Sordet, Tatiana Sotnikova, Jorge Alberto Spindler, Javier Walter Spindler, Marina Stanislav, Gerald Stapfer, Mayya Starovoytova, Virginia Steen, Simona Szasz, Guillermo Tate, Patricio Tate, Piia Tuvik, Adelfia Quezada Urenda, Lyalya Valishina, Amber Vanhaecke, Brenda Vázquez, Ildiko Vicsi, Barbara Vigone, Oana Vutcanu, René Westhovens, Victoria Zimina, Anna Zubrzycka-Sienkiewicz. Primary investigators are highlighted in bold.
Contributors YA and CPD contributed to the study concept and design, and data collection, analysis and interpretation. PW contributed to the study concept and design, data analysis and interpretation. DK, CE, FM and AL contributed to data analysis and interpretation. CS contributed to the study concept and design and data interpretation. RB designed the study analyses and contributed to data interpretation. All authors contributed to manuscript preparation and approved the final version.
Funding The study was funded by Sanofi R&D, France.
Competing interests YA reports personal fees from Actelion, Bayer, BMS and Curzion, and grants and personal fees from Inventiva, Roche and Sanofi. CPD reports personal fees from Actelion, Bayer, Boehringer Ingelheim, Corbus, Roche, Sanofi, and grants and personal fees from CSL Behring, GlaxoSmithKline and Inventiva. DK reports personal fees from Acceleron, Actelion, Blade Therapeutics, Eicos Sciences, Inc, Galapagos, GlaxoSmithKline, Mitsubishi Tanabe, Sanofi-Aventis/Genzyme and UCB Pharma, and grants and personal fees from Bayer, Bristol Myers Squibb and Genentech/Roche; he is funded by the NIH/NIAMS K24 AR063120. PW, CS, CE, FM, RB and AL are employees of Sanofi. CS is a shareholder in Sanofi.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Patient consent for publication Obtained.
Ethics approval The study was conducted in accordance with Declaration of Helsinki and International Conference of Harmonisation guidelines for Good Clinical Practice. Each participating site’s institutional review board or ethics committee approved the protocol and amendment(s) (online supplemental table S2).
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. Qualified researchers may request access to patient level data and related study documents, including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan and dataset specifications. Patient level data will be anonymised, and study documents will be redacted to protect the privacy of study participants. Further details on Sanofi’s data sharing criteria, eligible studies and process for requesting access can be found at: https://www.clinicalstudydatarequest.com.
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