TY - JOUR
T1 - Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy
T2 - 12-month results of an open-label extension study
AU - patisiran Global OLE study group
AU - Adams, David
AU - Polydefkis, Michael
AU - González-Duarte, Alejandra
AU - Wixner, Jonas
AU - Kristen, Arnt V.
AU - Schmidt, Hartmut H.
AU - Berk, John L.
AU - Losada López, Inés Asunción
AU - Dispenzieri, Angela
AU - Quan, Dianna
AU - Conceição, Isabel M.
AU - Slama, Michel S.
AU - Gillmore, Julian D.
AU - Kyriakides, Theodoros
AU - Ajroud-Driss, Senda
AU - Waddington-Cruz, Márcia
AU - Mezei, Michelle M.
AU - Planté-Bordeneuve, Violaine
AU - Attarian, Shahram
AU - Mauricio, Elizabeth
AU - Brannagan, Thomas H.
AU - Ueda, Mitsuharu
AU - Aldinc, Emre
AU - Wang, Jing Jing
AU - White, Matthew T.
AU - Vest, John
AU - Berber, Erhan
AU - Sweetser, Marianne T.
AU - Coelho, Teresa
AU - Vita, Giuseppe
AU - Rizzo, Vincenzo
AU - Russo, Massimo
AU - Mazzeo, Anna
AU - Gentile, Luca
AU - Brueckner, Caitlin
AU - Lazzari, Victoria
AU - Wiesman, Janice
AU - DeLong, Douglas
AU - Victory, Jennifer
AU - Dalton, James
AU - May, John
AU - Gilmore, Catherine
AU - Diallo, Saran
AU - Delmont, Emilien
AU - Pouget, Jean
AU - Verschueren, Annie
AU - Grapperon, Aude Marie
AU - Campana-Salort, Emmanuelle
AU - Lopate, Glenn
AU - Florence, Julaine
N1 - Funding Information:
DA reports consultancy fees and institutional grants from Alnylam Pharmaceuticals and Pfizer, and symposium honoraria from Pfizer, outside of the submitted work. SA-D reports personal fees from Alnylam Pharmaceuticals outside of the submitted work. SA reports grants from Alnylam Pharmaceuticals and Pfizer outside of the submitted work. JLB acknowledges study investigator and coordination time and hospital services compensation from Alnylam Pharmaceuticals for the work under consideration; personal fees for a visiting professor presentation from Alnylam Pharmaceuticals, advisory committee from Akcea Therapeutics, study investigator and coordinator compensation from Pfizer, and scientific advisory board fees from Intellia Therapeutics and Corino Therapeutics outside of the submitted work. THB reports grants and personal fees from Alnylam Pharmaceuticals during the conduct of the study; grants and personal fees from Ionis Pharmaceuticals and personal fees from Akcea Therapeutics and Pfizer outside of the submitted work. TC reports financial support to attend scientific meetings from Pfizer and personal fees from Alnylam Pharmaceuticals and Akcea Therapeutics outside of the submitted work. IMC reports primary investigator fees from Alnylam Pharmaceuticals during the conduct of the study and consultancy fees from Pfizer and Ionis Pharmaceuticals and primary investigator fees from Ionis Pharmaceuticals outside the submitted work. AD acknowledges research funding from Pfizer, Celgene Corporation, Alnylam Pharmaceuticals, Takeda Pharmaceuticals, Akcea Therapeutics, and Prothena Corporation; advisory board fees from Caelum Biosciences; and institutional funding for advisory board participation from Intellia Therapeutics outside of the submitted work. JDG reports institutional grants from Alnylam Pharmaceuticals during the conduct of the study and honoraria for an expert advisory board from Alnylam Pharmaceuticals outside the submitted work. AG-D reports consultancy fees from Alnylam Pharmaceuticals and Pfizer outside of the submitted work. AVK reports honoraria and fees for lectures and speakers' bureaus. IALL acknowledges personal fees, non-financial support, and other support outside of the submitted work. EM reports honorarium paid to her institution (Mayo Clinic) from Alnylam Pharmaceuticals for symposium speaking. MMM reports honorarium for poster presentation and principal investigator fees from Alnylam Pharmaceuticals during the conduct of the study; speaker and advisory board fees from Alnylam Pharmaceuticals, Akcea Therapeutics, and Pfizer; and non-financial support from Alnylam Pharmaceuticals outside of the submitted work. VP-B reports principal investigator and advisory board fees from Alnylam Pharmaceuticals and principal investigator and symposium speaker fees from Akcea Therapeutics, during the conduct of the study. MP acknowledges consultancy and principal investigator fees from Alnylam Pharmaceuticals in relation to this work and consultancy and principal investigator fees from Alnylam Pharmaceuticals and Ionis Pharmaceuticals, and consultancy fees from Eidos and Pfizer outside of the submitted work. DQ reports grants, personal fees, and non-financial support from Alnylam Pharmaceuticals; grants and non-financial support from Pfizer and Cytokinetics; and grants from Ionis, Momenta, and Argenx during the conduct of the study. MSS reports consultancy fees and symposium and advisory board participation honoraria from Alnylam Pharmaceuticals and Pfizer outside of the submitted work. MU acknowledges personal fees and non-financial support for advisory board participation, travel, and speaking from Alnylam Pharmaceuticals and Pfizer outside the submitted work. MW-C reports honorarium from NHI, Prothena Corporation, FoldRx, Ionis Pharmaceuticals, Pfizer, Alnylam Pharmaceuticals, PTC, and Genzyme for travel expenses related to presentations at medical meetings; for acting as a principal investigator in clinical trials; and as a consultant, outside of the submitted work. JW reports advisory board and lecture fees from Alnylam Pharmaceuticals, Pfizer, and Akcea Therapeutics outside of the submitted work. EA, MTSw, JV, and MTW are employees of Alnylam Pharmaceuticals; in addition, EA, MTSw, JV, and MTW have stock options and EA, MTSw, JV, and MTW have stocks. EB and JJW are former employees of Alnylam Pharmaceuticals and had stock options. All other authors declare no competing interests.
Funding Information:
This study was funded by Alnylam Pharmaceuticals (Cambridge, MA, USA). The authors thank the patients and their families for their valued contribution to this study. The authors would also like to thank the patisiran global OLE study group listed in the appendix (p 11) ). The authors thank Jennifer L S Willoughby, Katherine Alfond, and Anastasia McManus, of Alnylam Pharmaceuticals for editorial assistance. The authors acknowledge the medical writing services provided by Ed Childs of Adelphi Communications (Macclesfield, UK), in accordance with the Good Publication Practice guidelines, funded by Alnylam Pharmaceuticals.
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2021/1
Y1 - 2021/1
N2 - Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change –4·0, 95 % CI –7·7 to −0·3; phase 2 OLE patisiran –4·7, –11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment −1·4, 95% CI –6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran. Funding: Alnylam Pharmaceuticals.
AB - Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change –4·0, 95 % CI –7·7 to −0·3; phase 2 OLE patisiran –4·7, –11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment −1·4, 95% CI –6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran. Funding: Alnylam Pharmaceuticals.
UR - http://www.scopus.com/inward/record.url?scp=85097405151&partnerID=8YFLogxK
U2 - 10.1016/S1474-4422(20)30368-9
DO - 10.1016/S1474-4422(20)30368-9
M3 - Article
C2 - 33212063
AN - SCOPUS:85097405151
VL - 20
SP - 49
EP - 59
JO - The Lancet Neurology
JF - The Lancet Neurology
SN - 1474-4422
IS - 1
ER -