Two Phase 3 Trials of Gantenerumab in Early Alzheimer's Disease
- Authors: Bateman, Randall J; Smith, Janice; Donohue, Michael C; Delmar, Paul; Abbas, Rachid; Salloway, Stephen; Wojtowicz, Jakub; Blennow, Kaj; Bittner, Tobias; Black, Sandra E; Klein, Gregory; Boada, Mercè; Grimmer, Timo; Tamaoka, Akira; Perry, Richard J; Turner, R Scott; Watson, David; Woodward, Michael; Thanasopoulou, Angeliki; Lane, GRADUATE I and II Investigators and the Gantenerumab Study Group: Jeffery L Cummings, Randall Bateman, Kaj Blennow, Mercè Boada, Michael C Donohue, Nick C Fox, Takeshi Iwatsubo, Stephen Salloway, Philip Scheltens, Reisa Sperling, Bruno Vellas, Dennis Cordato, William Huynh, Raymond Schwartz, Roger Clarnette, Sarah Leishman, Cate Mansfield, Bruce Brew, Denis Crimmins, Anna Schutz, Jonathan Strum, Sanka Amadoru, Andrew Huynh, Kathryn Lee, Thinza Moe, Irene Tan, Michael Woodward, Paul Yates, Henry Zeimer, Ishita Batta, Edmund Cheong, Cathy Short, Ashlesha Vaidya, Boschetti Gabriela, Lima Plinio, Twardowschy Carlos, Augustin Marina, Castilhos Raphael, Chaves Marcia, Perin Daiana, Amado Daniel, Sonia Maria Brucki, Merlin Silvia, Takada Leonel, Hoffmann Murilo, Pedro Kowacs, Amanda Machado, Antonio Carlos da Silva, Adolf Franco, Monica Fritzen, Giovanna Menin, Giovanna Silva, Sandra Black, Benjamin Lam, Corinne Fischer, Michael Borrie, Elizabeth Finger, Stephen Pasternak, Jennie Wells, Howard Chertkow, Durjoy Lahiri, Wenhao Sun, Yue Wang, Mengya Xing, Yanwei Xu, Li Yang, Xiaoxia Chen, Jie Cheng, Zhenguo Liu, Zhiyin Lou, Mingming Xu, Yang Lv, Keliang Chen, Qiang Dong, JIntai Yu, Tingyi Feng, Ya Feng, Chunni Guo, Ye Liu, Mengyao Qui, Yuncheng Wu, Xiaoying Zhu, Qidong Chen, Jun Xu, Xueping Chen, Yanbing Hou, Ruwei Ou, Huifang Shang, Qianqian Wei, Lingyu Zhang, Yulei Deng, Suzhen Lin, Jun Liu, Wei Xu, Xiaomeng Xu, Wei Cheng, Qian Gong, Yanhua Qin, Lili Wei, Yinghun Zhang, Zhenwei Zhu, Wenting Fang, Yingqing Wang, Jiawei Xin, Qinyong Ye, Erhan Yu, Juan Ao, Haobo Chen, Aihua Guo, Minchao He, Jianxi Hu, Rong Hu, Yingjun Ouyang, Xiaoping Pan, Xiaojun Wen, Huili Zhang, Sifei Huang, Zhiheng Huang, Lijuan Wang, Fan Yang, Jiehao Zhao, Dantao Peng, Yanxing Chen, Zhirong Liu, Qingqing Tao, Yaping Yan, Baorong Zhang, Jiong Zhou, X I Cheng, Yuping Ma, Qi Niu, Yujie Shen, Wenping Yang, Huihui Zhao, Min Li, Xu Liu, Zhenyu Tang, Ye Yu, Hongmei Zeng, Junran Liu, Xiuqing Pan, Mingrong Xia, Ali Yang, Jiewen Zhang, Jincai He, Leiyu Geng, Cancan He, Xiaoli Li, Qingguo Ren, Hao Shu, Zan Wang, Di Wu, Chunming Xie, Li Zhang, Zhengsheng Zhang, Zhijun Zhang, Hong Zhou, Dan Zhu, Lanlan Chen, Xiaobo Li, Cancan Ma, Lu Wang, Mengmei Yin, Kai Wang, Ling Wei, Xingqi Wu, Shanshan Zhou, Lei He, Xiaoming Rong, Qingyu Shen, Hongxuan Wang, Yidong Wang, Ling Li, Haibing Xiao, Liang Cui, Jianliang Fu, Qihao Guo, Cheng Hu, Xiaokang Sun, Shankai Yin, Jiehua Zhu, Haifeng Chen, Lai Qian, Ruomeng Qin, Yun Xu, Hui Zhao, Yuqin Cao, Zhaozhao Cheng, Xinyi Lv, Mengyue Ruan, Qiong Wang, Shuxia Wang, Yuan Fang, Xia Li, Xiang Lin, Qi Qiu, Ning Su, Jinghua Wang, Feng Yan, Yintai Fan, Chengwei Guo, Qinge Zhang, Ya-Fang Chen, Ming-Jang Chiu, Yi-Hui Kao, Chin-Chang Huang, Kuo-Lun Huang, Kun-Ju Lin, Chiung-Chih Chang, Wen-Neng Chang, Chi-Wei Huang, Shu-Hua Huang, Shih-Wei Hsu, Jun-Jun Lee, Chia-Yi Lien, Ming-Kung Wu, Mei- Chuan Chou, Ping-Song Chou, Cheng-Fang Hsieh, Chiou-Lian Lai, Chien-Hsun Li, Meng-Ni Wu, Jui-Cheng Chen, Kuan-Fei Chen, Yuh-Cherng Guo, Yi-Ting Hsu, Hui-Chun Huang, Wei-Shih Hunag, Fu-Yu Lin, Kang-Hsu Lin, Ching-Hua Lu, Ming-Kuei Lu, Chon-Haw Tsai, Yu-Wan Yang, Daniela Andruita, Melanie Barbay, Agnes Devendeville, Olivier Godefroy, Maite Formaglio, Helene Mollion, Jing Xie, Pierre Krolak-Salmon, Mathieu Ceccaldi, Claude Gueriot, Emmanuel Cognat, Julian Dumurgier, Sinead Gaubert, Claire Hourregue, Jaques Hugon, Claire Paquet, Pierre Anthony, Frederic Blanc, Catherine Demuynck Roegel, Nathalie Phillipi, Alix Ravier, Catherine Faisant, Francoise Lala Montrauriol, Pierre-Jean Ousset, Nathalie Sastre Henga
- Publication year: 2023
- Type: Articolo in rivista
- OA Link: http://hdl.handle.net/10447/673186
Abstract
Background: Monoclonal antibodies that target amyloid-beta (Aβ) have the potential to slow cognitive and functional decline in persons with early Alzheimer's disease. Gantenerumab is a subcutaneously administered, fully human, anti-Aβ IgG1 monoclonal antibody with highest affinity for aggregated Aβ that has been tested for the treatment of Alzheimer's disease. Methods: We conducted two phase 3 trials (GRADUATE I and II) involving participants 50 to 90 years of age with mild cognitive impairment or mild dementia due to Alzheimer's disease and evidence of amyloid plaques on positron-emission tomography (PET) or cerebrospinal fluid (CSF) testing. Participants were randomly assigned to receive gantenerumab or placebo every 2 weeks. The primary outcome was the change from baseline in the score on the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater cognitive impairment) at week 116. Results: A total of 985 and 980 participants were enrolled in the GRADUATE I and II trials, respectively. The baseline CDR-SB score was 3.7 in the GRADUATE I trial and 3.6 in the GRADUATE II trial. The change from baseline in the CDR-SB score at week 116 was 3.35 with gantenerumab and 3.65 with placebo in the GRADUATE I trial (difference, -0.31; 95% confidence interval [CI], -0.66 to 0.05; P = 0.10) and was 2.82 with gantenerumab and 3.01 with placebo in the GRADUATE II trial (difference, -0.19; 95% CI, -0.55 to 0.17; P = 0.30). At week 116, the difference in the amyloid level on PET between the gantenerumab group and the placebo group was -66.44 and -56.46 centiloids in the GRADUATE I and II trials, respectively, and amyloid-negative status was attained in 28.0% and 26.8% of the participants receiving gantenerumab in the two trials. Across both trials, participants receiving gantenerumab had lower CSF levels of phosphorylated tau 181 and higher levels of Aβ42 than those receiving placebo; the accumulation of aggregated tau on PET was similar in the two groups. Amyloid-related imaging abnormalities with edema (ARIA-E) occurred in 24.9% of the participants receiving gantenerumab, and symptomatic ARIA-E occurred in 5.0%. Conclusions: Among persons with early Alzheimer's disease, the use of gantenerumab led to a lower amyloid plaque burden than placebo at 116 weeks but was not associated with slower clinical decline. (Funded by F. Hoffmann-La Roche; GRADUATE I and II ClinicalTrials.gov numbers, NCT03444870 and NCT03443973, respectively.).