Impact of Vutrisiran on Quality of Life and Physical Function in Patients with Hereditary Transthyretin-Mediated Amyloidosis with Polyneuropathy
Laura Obici, Senda Ajroud‐Driss, Kon‐Ping Lin, John L. Berk, Julian D. Gillmore, Parag Kale, Haruki Koike, David Danese, Emre Aldinc, Chongshu Chen, John Vest, David Adams, the HELIOS-A Collaborators Study Group, Jonas Wixner, Rolf Backlund, Björn Pilebro, Intissar Anan, Fredrik Edbom, Anna Ekman, Sandra Arvidsson, Ulrika H. Englund, Karin Söderberg, Erik Nordh, Erica Uneus, Kristin Samuelsson, A Nilzén, Rayomand Press, Mirjam Bilecen, Teresa Coelho, Marta Novais, Patrícia Rodrigues, Ana Silva, Inês Lopes Cardoso, Carla Rodrigues, Joana Ramalho, Helder Martins, Mónica G. Silva, Nádia Guimarães, Javier Martínez Pérez, Antonio Hipólito Reis, Julia R Monte, Natália Ferreira, Cristina Alves, Márcio Cardoso, Ricardo Cotrin Teixeira, Isabel Conceição, Filipa Lamas, Miguel Oliveira Santos, Catarina Falcão de Campos, Conceição de Azevedo Coutinho, José Castro, Isabel Castro, Daniela Rodrigues Silva, Susana Gonçalves, Eleonora Di Buduo, Claudia Sforzini, Roberta Mussinelli, Vittorio Rosti, Alessandro Lozza, Anna Racchi, Mario Sabatelli, Marco Luigetti, Giulia Bisogni, Ângela Romano, Valeria Guglielmino, Andrea Di Paolantonio, Daniela Bernardo, Giuseppe Vita, Anna Mazzeo, Massimo Russo, Davide Pareyson, Daniela Calabrese, Silvia Fenu, Paola Saveri, Hans Nienhuis, Geert Bokhorst, Carlien Roos, Margriet Couperus, Greetje de Jong, Anne F. Brunger, Gea Drost, Fiete Lange, Adinda Colauto, Márcia Waddington‐Cruz, Aline França de Abreu, Roberto Coury Pedrosa, Renata Gervais de Santa Rosa, Moisés Dias, Fetra Rakotondratafika, Andoni Echaniz‐Laguna, Cécile Cauquil, Céline Labeyrie, Guillemette Beaudonnet, Yasmine Boubrit, Amina Gaouar, Halima Bourenane, Shahram Attarian, El Khansa Yahia, Annie Verschueren, Aude‐Marie Grapperon
Abstract
Hereditary transthyretin (ATTRv; v for variant) amyloidosis, also known as hATTR amyloidosis, is a progressive and fatal disease associated with rapid deterioration of physical function and patients' quality of life (QOL). Vutrisiran, a subcutaneously administered RNA interference (RNAi) therapeutic that reduces hepatic production of transthyretin, was assessed in patients with ATTRv amyloidosis with polyneuropathy in the pivotal HELIOS-A study. The phase 3 open-label HELIOS-A study investigated the efficacy and safety of vutrisiran in patients with ATTRv amyloidosis with polyneuropathy, compared with an external placebo group from the APOLLO study of the RNAi therapeutic patisiran. Measures of QOL and physical function were assessed. At month 18, vutrisiran improved Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) total score (least squares mean difference [LSMD] in change from baseline [CFB]: –21.0; p = 1.84 × 10 –10 ) and Norfolk QOL-DN domain scores, compared with external placebo. This benefit relative to external placebo was evident across all baseline polyneuropathy disability (PND) scores and most pronounced in patients with baseline PND scores I–II. Compared with external placebo, vutrisiran also demonstrated benefit in EuroQoL-Visual Analog Scale (EQ-VAS) score (LSMD in CFB: 13.7; nominal p = 2.21 × 10 –7 ), 10-m walk test (LSMD in CFB: 0.239 m/s; p = 1.21 × 10 –7 ), Rasch-built Overall Disability Score (LSMD in CFB: 8.4; p = 3.54 × 10 –15 ), and modified body mass index (mBMI) (LSMD in CFB: 140.7; p = 4.16 × 10 –15 ) at month 18. Overall, Norfolk QOL-DN, EQ-VAS, and mBMI improved from pretreatment baseline with vutrisiran, whereas all measures worsened from baseline in the external placebo group. At month 18, Karnofsky Performance Status was stable/improved from baseline in 58.2/13.1% with vutrisiran versus 34.7/8.1% with external placebo. Vutrisiran treatment provided significant clinical benefits in multiple measures of QOL and physical function in patients with ATTRv amyloidosis with polyneuropathy. Benefits were most pronounced in patients with earlier-stage disease, highlighting the importance of early diagnosis and treatment. ClinicalTrials.gov: NCT03759379.