Five-Year Results With Patisiran for Hereditary Transthyretin Amyloidosis With Polyneuropathy
Authors: David Adams, Jonas Wixner, Michael Polydefkis, John L. Berk, Isabel M. Conceição, Angela Dispenzieri, Amanda Peltier, Mitsuharu Ueda, Shaun Bender, Kelley Capocelli, Patrick Y. Jay, Elena Yureneva, Laura Obici, Giuseppe Vita, Vincenzo Rizzo, Massimo Russo, Anna Mazzeo, Luca Gentile, John L Berk, Janice Wiesman, Michelle Kaku, Vincent Lau, Douglas DeLong, James Dalton, John May, Shahram Attarian, Emilien Delmont, Jean Pouget, Annie Verschueren, Aude-Marie Grapperon, Emmanuelle Campana-Salort, Isabel M Conceição, Carlos Neves, Miguel O Santos, Conceição de Azevedo Coutinho, Catarina Falcao de Campos, Teresa Coelho, Antonio H Reis, Nuno Correia, Javier M Perez, Ana Martins da Silva, Cristina Alves, Marcio Cardoso, Katia Valdrez, Julia R Monte, Marta Novais, Nadia Guimaraes, Ines Cardoso, Monica Freitas, Joana Ramalho, Natalia Ferreira, Daisuke Kuzume, Masahiro Yamasaki, Yuko Morimoto, Celine Tard, Eric Hachulla, Clement Gauvain, Maria-Claire Migaud-Chervy, Dominique Deplanque, Elsa Jozefowicz, Loic Lebellec, David Adams, Marie Théaudin-Saliou, Cécile Cauquil-Michon, Celine Labeyrie, Adeline Not, Abdallah Al-Salameh, Anne-Lise Lecoq, Maeva Stephant, Andoni Echaniz-Laguna, Laurent Becquemont, Guillemette Beaudonnet, Vincent Algalarrondo, Ludivine Eliahou, Michel S Slama, Antoine Rousseau, Aissatou Signate, Paola Darche, Jerome Grimaud, Emeline Berthelot, Jocelyn Inamo, Violaine Planté-Bordeneuve, Thierry Gendre, Raphaele Arrouasse, Samar S Ayache, Laura Ernande, Philippe Le Corvoisier, Hayet Salhi, Ariane Choumert, Cyril Charlin, Thomas Megelin, Thomas H Brannagan III, Steven Tsang, Fernanda Wajnsztajn, Jeffrey Shije, Christina Ulane, Inna Kleyman, Louis Weimer, Comana Cioroiu, Kleopas Kleopa, Eleni Zamba-Papanicolaou, Satoshi Tada, Masahiro Nagai, Rina Ando, Yuki Yamanishi, J Scott Overcash, Sinikka Green, Michael Waters, Derya J Coskun, Paul Manos, Karla A Zepeda, William O’Riordan, Laura Obici, Andrea Cortese, Alessandro Lozza, Giampaolo Merlini, Vittorio Rosti, Mario Sabatelli, Giulia Bisogni, Daniela Bernardo, Marco Luigetti, Andrea Di Paolantonio, Valeria Guglielmino, Angela Romano, Hans Nienhuis, Arnt V Kristen, Christian Nagel, Fabian aus dem Siepen, Selina Hein, Shuichiro Neshige, Josep M Campistol, Lida Maria Rodas Marin, Josep Miquel Blasco Pelicano, Lucía Galán Dávila, Vanesa Pytel Cordoba, Antonio Guerrero Sola, Alejandro Horga, Julián García Feijoo, Leopoldo Perez de Isla, Wilson Marques Júnior, Carolina Lavigne Moreira, Vanessa Daccach Marques, Francisco Munoz Beamud, Cristina Borrachero, Inés AL López, Monica Sanz, Elena Rigo Oliver, Juan González Moreno, Jose M Gamez Martinez, Cristina Descals, Mercedes Uson, Francisco Jose Vega, Antoni Figuerola, Carles Montala, Márcia Waddington-Cruz, Aline Souza de Abreu, Moises Dias da Silva, Renata Gervais de Santa Rosa, Marcus Vinicius Pinto, Amanda Cardoso Berensztejn, Luiz Felipe Pinto, Mariana de Andrade Guedes, Fabio Barroso, Andrea Lautre, Lucas G Orellana, Maria Alejandra González-Duarte Briseño, Karla Cárdenas-Soto, Carlos Gerardo Cantú Brito, David Rivera de la Parra, Jose Pablo Hernandez Reyes, Maria del Mar Saniger Alba, Yesim Parman, Erdi Sahin, Nail G Serbest, Hacer Durmus, Arman Cakar, Sacit Karamursel, Ali Elitok, Nermin G Sirin Inan, Emre Altinkurt, Michael Polydefkis, Adriane C Allen, Vinay Chaudhry, Raquel Jarrett, Neil Bressler, Mandeep Singh, Mohammad Khoshnoodi, Daniel P Judge, Alvin T Lui, Tae Hwan Chung, Geno Vista, Syed Mahmood Shah, Hirotoshi Hamaguchi, Tetsuya Oda, Masahiro Shimomura, Christof Scheid, Udo Holtick, Jeeyoung Oh, Hee Jin Kim, Hyun Jin Shin, Kyomin Choi, Mitsuharu Ueda, Yohei Misumi, Toshiya Nomura, Takahisa Tateishi, Elizabeth A Mauricio, Elliot Dimberg, Leslie T Cooper, Angela Dispenzieri, Amie Fonder, Miriam Hobbs, Peter Dyck, Wilson Gonsalves, Nelson Leung, Thomas E Witzig, Lisa Hwa, Prashant Kapoor, Shaji K Kumar, Yi Lin, Vincent S Rajkumar, David Dingli, Morie A Gertz, Peter J Dyck, Linde Gove, Samir Dalia, David Croy, Tim Holding, Peter Gorevic, Chi-Chao Chao, Ming-Jen Lee, Jen-Jen Su, Sung-Tsang Hsieh, Li-Kai Tsai, Shin-Joe Yeh, Chih-Chao Yang, Chao-Wen Lin, Senda Ajroud-Driss, Robert Sufit, John-Michael Li, Miriam Freimer, Samantha LoRusso, Yasuhiro Aso, Byoung-Joon Kim, JuHyeon Kim, Ga Yeon Lee, Eun Bin Cho, Eun-Seok Jeon, Ju-Hong Min, Jin Myoung Seok, Hye Lim Lee, Jae Hong Park, Yoshiki Sekijima, Nagaaki Kato, Dai Kishida, Akiyo Hineno, Minori Kodaira, Tsuneaki Yoshinaga, Ken Takasone, Teruyoshi Miyahara, Yusuke Takahashi, Akira Imai, Kazuhiko Matsumoto, Kon-Ping Lin, Yi-Chung Lee, Jonas Wixner, Bjorn Pilebro, Ole Suhr, Intissar Anan, Erik Nordh, Fatima Pedrosa-Domellöf, Maria Chermenina, Anneli Nygren, Ivaylo Tournev, Sashka Zhelyazkova-Glaveeva, Zheyna Cherneva, Staiko Sarafov, Teodora Chamova, Sylvia Cherninkova-Gopina, Hartmut H Schmidt, Elena Vorona, Anna Huesing-Kabar, Matthias Schilling, Iyad Kabar, Phil-Robin Tepasse, Julian D Gillmore, Ana Martinez-Naharro, Liza Chacko, Oliver Cohen, Steven Law, Tamer Rezk, Helen J Lachmann, Dianna Quan, Stacy Dixon, Vera Fridman, Soon Chai Low, Khean Jin Goh, Michelle M Mezei, Kristin Jack, N. Kevin Wade, Glenn Lopate, Stephanie Geisler, R. Brian Sommerville, Julaine Florence, Graeme Stewart, Mark Taylor, Daniel Suan
Journal: JAMA Neurology (2025)

Importance There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN. Objective To present the long-term efficacy and safety of patisiran in adults with hATTR-PN. Design, Setting, and Participants This global open-label extension (OLE) of the APOLLO randomized clinical trial and phase 2 OLE study enrolled patients from 43 hospitals or clinical centers across 19 countries between July 2015 and August 2017, with follow-up until November 2022. Of 212 eligible patients with hATTR who completed the phase 3 APOLLO or phase 2 OLE parent studies, 211 enrolled in and 138 completed the global OLE. Intervention Patisiran, 0.3 mg/kg, intravenously once every 3 weeks for up to 5 years. Main Outcomes and Measures Outcomes evaluated at year 5 of the global OLE included disability (polyneuropathy disability [PND] score); polyneuropathy severity (Neuropathy Impairment Score [NIS]), nutritional status (modified body mass index [mBMI]), quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN]), and Rasch-Built Overall Disability Scale (R-ODS), with no statistical hierarchy. Safety, survival probability, and mortality were also assessed. Results At the global OLE baseline, the mean (SD) age was 61.3 (12.3) years, and 156 patients (73.9%) were male. In 138 patients completing the study, PND scores remained stable or improved in 89 patients (65.0%), NISs showed a mean (SD) change of 10.9 (14.7), and mean (SD) mBMI (calculated as weight in kilograms divided by height in meters squared times serum albumin in grams per liter) increased by 46.4 (120.7) over 5 years from baseline. Norfolk QOL-DN and R-ODS scores showed mean (SD) changes of 4.1 (16.7) and –3.7 (6.2), respectively. Adverse events (AEs) leading to study withdrawal occurred in 47 patients (22.3%). Infusion-related reactions were the most common treatment-related AE (n = 34 [16.1%]). Overall, 41 patients (19.4%) died during the study. Patisiran treatment in the parent study and low familial amyloid polyneuropathy score at parent study baseline were associated with significantly improved survival. Conclusions and Relevance In the longest study of an RNAi therapeutic for any disease, patisiran treatment resulted in modest changes for patients with hATTR-PN with an acceptable safety profile. These results highlight the importance of initiating early treatment for hATTR and the potential of RNAi therapeutics in medicine. Trial Registration ClinicalTrials.gov Identifier: NCT02510261