Safety and efficacy of a fitusiran antithrombin-based dose regimen in people with hemophilia A or B: the ATLAS-OLE study
Year: 2025
Type: article
Abstract: ABSTRACT: Fitusiran, a subcutaneous investigational small interfering RNA therapeutic, lowers antithrombin (AT) to increase thrombin generation and rebalance hemostasis in people with hemophilia. This phase 3 open-label extension study (ATLAS-OLE) evaluated safety and efficacy of an AT-based dose regimen (AT-DR) in males aged ≥12 years with severe hemophilia A/B, with/without inhibitors. The original dose regimen (ODR) of 80 mg monthly was optimized to AT-DR targeting AT activity levels 15% to 35% to mitigate thrombotic risk (starting dose of 50 mg once every 2 months, individually adjusted to 20 mg once every 2 months, or 20/50/80 mg monthly as needed). Primary and secondary end points were safety and efficacy, respectively. Integrated safety analyses assessed safety of AT-DR and ODR across all fitusiran studies and integrated efficacy analyses compared efficacy of AT-DR in ATLAS-OLE with phase 3 parent study control groups. At interim data cutoff, 213 participants were enrolled on AT-DR (78% on regimens of once every 2 months). Integrated safety analyses of participants receiving AT-DR (n = 286) demonstrated that AT-DR was well tolerated. In ATLAS-OLE, median observed annualized bleeding rate (ABR) with AT-DR was 3.7 (interquartile range, 0.0-7.5). Integrated efficacy analyses demonstrated superiority of AT-DR over on-demand clotting factor concentrates (CFCs; 71% mean ABR reduction; P < .0001), and on-demand bypassing agents (BPAs; 73% mean ABR reduction; P = .0006); improvement over BPA prophylaxis (70% mean ABR reduction); and ABR comparable with that observed with CFC prophylaxis. Fitusiran AT-DR was well tolerated and maintained bleed protection with as few as 6 injections per year. This trial was registered at www.ClinicalTrials.gov as #NCT03754790.
Source: Blood
Authors: Guy Young, Kaan Kavakli, Robert Klamroth, Tadashi Matsushita, Flora Peyvandi, Steven W. Pipe, Savita Rangarajan, Ming-Ching Shen, Alok Srivastava, Jing Sun, Huyen Tran, Chur-Woo You, Bülent Zülfikar, Laurel A. Menapace, Chuanwu Zhang, Yuqian Shen, Marja Puurunen, Marek Demissie, Gili Kenet, Teh-Liane Khoo, Scott Dunkley, Stephanie P'ng, Dominic Pepperell, Stephanie Lam, Elizabeth Steinepreis, Jacques Malherbe, Tulene Kendrick, Marcus Lombard, Huyen Tran, Jessie Zhao, Hannah Stevens, Caroline Dix, James McFadyen, Jean St-Louis, Jeannine Kassis, Georges Rivard, Jing Sun, Xiaofang Li, Huiping Li, Jieyu Ye, Xuan Zhou, Dong Du, Xuefeng Wang, Jing Dai, Quilan Ding, Wenman Wu, Yiyi Lu, Runhui Wu, Guoqing Liu, Wanru Yao, Yan Wang, Yunyun Wei, Weiqun Xu, Yu Du, Liyao Xu, Di Wang, Chan Liao, Hongwei Zhang, Ziqiang Yu, Hong Tian, Haibo Wang, Jie Yin, Tienan Zhu, Huacong Cai, Juan Xiao, Shujie Wang, Shufen Liu, Kaini Shen, Yun Chen, Yali Chang, Tan Sang, Jun Zhao, Yawei Zhou, Liya Zhai, Xiadong Qiu, Yulei He, Hui Li, Yi Xia, Min Zhou, Feng Gao, Shipin Feng, Xiaoli Luo, Dan Li, Zhongguang Cui, Chunzhu Zhao, Hong Xu, Lingjie Sun, Xue Shi, Xiaojing Zeng, Lu Qi, Shuyun Cao, Zeping Zhou, Fuhou Zhang, Lingmei Yin, Hongli Mu, Hui Bi, Zhengchao Li, Yaping Miu, Yaming Xi, Mingfeng Jia, Long Zhao, Xielan Zhao, Yaochun Li, Jie Peng, Chia-Yau Chang, Yen-Lin Liu, Ming-Ching Shen, Cheng-Wei Huang, Shih-Chung Wang, Hsuan-Yu Lin, Ching-Yeh Lin, Sheng-Chieh Chou, Ming-Kai Chuang, Szu-Chun Hsu, Jiaan-Der Wang, Ming-Yang Shih, Liang-Tsai Hsiao, Giun-Yi Hung, Hsiu-Ju Yen, Po-Shen Ko, Hung Chang, Shih-Hsaing Chen, Te-Fu Weng, Yu-Hua Chao, Sherig-Wei Zeng, Peter Kampmann, Eva Funding, Yesim Dargaud, Claude Negrier, Stéphanie Desag, Laurent Frenzel, Guillemette Fouquet, Cécile Bally, Robert Klamroth, Ana-Marija Orlovic, Christian Pfrepper, Michael Metze, Rima Chakaroun, Maria Weise, László Nemes, Agnes Ronatas, Cecil Ross, Seetharam Anandram, Vandana Bharadwaj, Sonali Salvi, Sunil Lohande, Alok Srivastava, Aby Abraham, Fouzia Aboobacker, Shailendra Verma, Gaurav Datta, Savita Rangarajan, Shweta Bansal, Shashikant Apte, Kannan Subramanian, Beatrice Nolan, Saad Ahmed, Niamh O’Connell, James O’Donnell, Kevin Ryan, Michelle Lavin, Gili Kenet, Omri Cohen, Mudi Misgav, Assaf Barg, Sarina Levy Mendelovich, Flora Peyvandi, Roberta Gualtierotti, Ezio Zanon, Luca Spiezia, Chiara Simion, Tadashi Matsushita, Shuichi Okamoto, Nobuaki Suzuki, Takeshi Kanematsu, Naruko Suzuki, Yuka Kawaguchi, Satoshi Higasa, Tazuko Tokugawa, Akihiro Sawada, Rie Shirayama, Masaru Kawamura, Hiroshi Asai, Koichi Oshida, Tetsuji Sato, Takuma Ito, Katsuyoshi Koh, Yoshitaka Mizushima, Takahiro Ishikawa, Hirohito Kubota, Ryota Kaneko, Tomoya Irikura, Mamoru Honda, Katsuaki Taira, Yuki Arakawa, Makiko Mori, Kohei Fukoka, Koichi Oshima, Yuichi Mitani, Yoshiaki Ogawa, Kiyoshi Ando, Rikio Suzuki, Ryujiro Hara, Yasuyuki Aoyama, Masako Toyosaki, Daisuke Ogiya, Shinichiro Machida, Hiroshi Kawada, Yukari Shirasugi, Makoto Onizuka, Ken Omachi, Kagehiro Amano, Tomoko Yamaguchi, Ei Kinai, Takeshi Hagiwara, Mihoko Yotsumoto, Ryoko Sekiya, Masato Bingo, Yushi Chikasawa, Akito Ichiki, Yoshiko Kamikubo, Ryui Miyashita, Takashi Muramatsu, Ho-Jin Shin, DoYoung Kim, Chur-Woo You, Ju Young Kim, Seung Min Hahn, Chuhl Joo Lyu, Jung Woo Han, Young Shil Park, Ja Hyang Cho, Azizan Shariq, Soo Min Lim, Lily Wong, Heng Chang Choo, Gilbert Wilfred, Mohd Tarmizi Ahmad Zakhi, Yin Man Lim, Khaiteri Raghunathan, Jameela Sathar, Syazarin Fidhora Nasution, Yee Yee Yap, Veena Selvaratnam, Daniel Malan, Zelda Erika Punt, Ali Bulent Antmen, Ilgen Sasmaz, Utku Aygunes, Kaan Kavakli, Nihal Karadas, Deniz Karapinar, Alphan Kupesiz, Mine Erkan, Kupesiz Funda Tayfun, Elif Guler, Bulent Zulfikar, Basak Koc, Vahap Okan, Sahin Handan Haydaroglu, Canan Albayrak, Ibrahim Kartal, Ebru Yilmaz, Musa Karakukcu, Ekrem Unal, Alper Ozcan, Fahri Sahin, Betul Tuzun, Guray Saydam, Ievgenii Averianov, Oksana Kovtunenko, Oleksandra Stasyshyn, Maksym Semerak, Orest Tushnytskyy, Kateryna Vilchevska, Iryna Bakhchyvandzhy, Nataliya Romanyuk, Stanislav Nikulin, Alina Kobets, Jayanthi Alamelu MRCPCH, Samah Babiker, Catherine Bagot, James Tyan Rodgers, Lisa Boggio, Mindy Simpson, Erin Cockrell, Candance DeBerry, Dana Obzut, John Fargo, Jeffrey Hord, Stephanie Savelli, Joseph Lasky, Jennifer Buitrago, Waseem Alhushki, Cynthia Gauger, Darren Klawinski, Eric Sandler, Scott Bradfield, Paul Pitel, Michael Joyce, Howard Katzenstein, Manisha Bansal, Allison Bechtel, Christine Knoll, Esteban Gomez, Shanna White, Sanjay Shah, Joanna Gendreau, Lori Wagner, Maa-Ohui Quarmyne, Larissa Bornikova, Colleen Cleary CNP, Pamela G. Hodges, Alexandra Mossali, Rachel Rosovsky, Victoria Turbini, Valerie Wood, Hanny Al-Samkari, Steven Pipe, Angela Weyand, Jordan Shavit, Amit Soni, Diane Nugent, Nina Hwang, Vanessa Salinas, Guy Young, Tom Hofstra, Jennifer Donkin, Jacquelyn Keegan, Zaheer Sibgha, Wendy Leung, Julie Jaffray
Institutions: University of Southern California, Children's Hospital of Los Angeles, Ege University, Vivantes Klinikum, Klinikum im Friedrichshain, Nagoya University Hospital, University of Milan, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Michigan, K. J. Somaiya Hospital & Research Centre, University of Southampton, National Taiwan University, National Taiwan University Hospital, Changhua Christian Hospital, St.John's Medical College Hospital, Nanfang Hospital, Southern Medical University, The Alfred Hospital, Monash University, Eulji University, Daejeon Eulji Medical Center, Eulji University, Eulji Medical Center, Istanbul University, Sanofi (United States), Tel Aviv University, Sheba Medical Center
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $5,500
OpenAlex ID: W4408214710