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