TY - JOUR
T1 - Analysis of autonomic outcomes in APOLLO, a phase III trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis
AU - González-Duarte, Alejandra
AU - Berk, John L.
AU - Quan, Dianna
AU - Mauermann, Michelle L.
AU - Schmidt, Hartmut H.
AU - Polydefkis, Michael
AU - Waddington-Cruz, Márcia
AU - Ueda, Mitsuharu
AU - Conceição, Isabel M.
AU - Kristen, Arnt V.
AU - Coelho, Teresa
AU - Cauquil, Cécile A.
AU - Tard, Céline
AU - Merkel, Madeline
AU - Aldinc, Emre
AU - Chen, Jihong
AU - Sweetser, Marianne T.
AU - Wang, Jing Jing
AU - Adams, David
N1 - Funding Information:
The study was funded by Alnylam Pharmaceuticals, Inc. Medical writing services provided by Kristen Brown (PhD) of Adelphi Communications Ltd, Macclesfield, UK were funded by Alnylam Pharmaceuticals, Inc. in accordance with Good Publication Practice (GPP3) guidelines. We would like to thank Anastasia McManus (Alnylam Pharmaceuticals, Inc.) for her assistance during preparation of this manuscript.
Funding Information:
The study was funded by Alnylam Pharmaceuticals, Inc. Medical writing services provided by Kristen Brown (PhD) of Adelphi Communications Ltd, Macclesfield, UK were funded by Alnylam Pharmaceuticals, Inc. in accordance with Good Publication Practice (GPP3) guidelines. We would like to thank Anastasia McManus (Alnylam Pharmaceuticals, Inc.) for her assistance during preparation of this manuscript.
Funding Information:
AGD reports serving as a consultant for Alnylam Pharmaceuticals and Pfizer. JB reports compensation for study investigator and coordinator time and hospital services from Alnylam Pharmaceuticals during the study. Outside of the submitted work, JB acknowledges personal fees from Alnylam Pharmaceuticals for visiting professor presentations, from Akcea Therapeutics for attendance at an advisory committee, from Intellia Therapeutics and Corino Therapeutics for scientific advisory boards and also reports study investigator and coordinator compensation from Pfizer Inc. DQ reports grants received from Alnylam Pharmaceuticals. MLM reports research grants from Alnylam Pharmaceuticals and Ionis Pharmaceuticals. HS has nothing to disclose. MP reports receiving personal fees and serving as a principal investigator and consultant for Alnylam Pharmaceuticals during the work. Outside of the study work MP reports personal fees, and serving as a principal investigator and consultant for Alnylam Pharmaceuticals, Ionis Pharmaceuticals, and Pfizer Inc. MWC received honoraria from NHI, Prothena, FoldRx, Akcea Therapeutics, Pfizer Inc., Alnylam Pharmaceuticals, PTC and Genzyme for travel expenses related to presentations at medical meetings, for acting as a consultant and as a principal investigator in clinical trials. MU reports personal fees and non-financial support for travel, participating in advisory boards, and speaker fees from Alnylam Pharmaceuticals and Pfizer Inc. outside of the submitted work. IC reports receiving personal fees and serving as a principal investigator for Alnylam Pharmaceuticals. AVK received honoraria and fees for lectures and speakers bureaus from Alnylam Pharmaceuticals, Akcea Therapeutics, and Pfizer Inc. TC reports personal fees from Alnylam Pharmaceuticals and personal fees and financial support to attend scientific meetings from Pfizer Inc., outside of the submitted work. CC acknowledges speaker honoraria from Alnylam Pharmaceuticals, Pfizer Inc., and Akcea Therapeutics, outside of the submitted work. CT has nothing to disclose. MM, EA, JC, MS, JJW are all employees of Alnylam Pharmaceuticals and MS reports owning Alnylam Pharmaceutical stock options. DA reports consultancy fees and clinical grants from Alnylam Pharmaceuticals, and clinical grants and symposium speaker fees from Pfizer Inc., outside of the submitted work.
Publisher Copyright:
© 2019, The Author(s).
PY - 2020/3/1
Y1 - 2020/3/1
N2 - Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, debilitating disease often resulting in early-onset, life-impacting autonomic dysfunction. The effect of the RNAi therapeutic, patisiran, on autonomic neuropathy manifestations in patients with hATTR amyloidosis with polyneuropathy in the phase III APOLLO study is reported. Patients received patisiran 0.3 mg/kg intravenously (n = 148) or placebo (n = 77) once every 3 weeks for 18 months. Patisiran halted or reversed polyneuropathy and improved quality of life from baseline in the majority of patients. At baseline, patients in APOLLO had notable autonomic impairment, as demonstrated by the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire autonomic neuropathy domain. At 18 months, patisiran improved autonomic neuropathy symptoms compared with placebo [COMPASS-31, least squares (LS) mean difference, − 7.5; 95% CI: − 11.9, − 3.2; Norfolk QOL-DN autonomic neuropathy domain, LS mean difference, − 1.1; − 1.8, − 0.5], nutritional status (modified body mass index, LS mean difference, 115.7; − 82.4, 149.0), and vasomotor function (postural blood pressure, LS mean difference, − 0.3; − 0.5, − 0.1). Patisiran treatment also led to improvement from baseline at 18 months for COMPASS-31 (LS mean change from baseline, − 5.3; 95% CI: − 7.9, − 2.7) and individual domains, orthostatic intolerance (− 4.6; − 6.3, − 2.9) and gastrointestinal symptoms (− 0.8; − 1.5, − 0.2). Rapid worsening of all study measures was observed with placebo, while patisiran treatment resulted in stable or improved scores compared with baseline. Patisiran demonstrates benefit across a range of burdensome autonomic neuropathy manifestations that deteriorate rapidly without early and continued treatment.
AB - Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, debilitating disease often resulting in early-onset, life-impacting autonomic dysfunction. The effect of the RNAi therapeutic, patisiran, on autonomic neuropathy manifestations in patients with hATTR amyloidosis with polyneuropathy in the phase III APOLLO study is reported. Patients received patisiran 0.3 mg/kg intravenously (n = 148) or placebo (n = 77) once every 3 weeks for 18 months. Patisiran halted or reversed polyneuropathy and improved quality of life from baseline in the majority of patients. At baseline, patients in APOLLO had notable autonomic impairment, as demonstrated by the Composite Autonomic Symptom Score-31 (COMPASS-31) questionnaire and Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire autonomic neuropathy domain. At 18 months, patisiran improved autonomic neuropathy symptoms compared with placebo [COMPASS-31, least squares (LS) mean difference, − 7.5; 95% CI: − 11.9, − 3.2; Norfolk QOL-DN autonomic neuropathy domain, LS mean difference, − 1.1; − 1.8, − 0.5], nutritional status (modified body mass index, LS mean difference, 115.7; − 82.4, 149.0), and vasomotor function (postural blood pressure, LS mean difference, − 0.3; − 0.5, − 0.1). Patisiran treatment also led to improvement from baseline at 18 months for COMPASS-31 (LS mean change from baseline, − 5.3; 95% CI: − 7.9, − 2.7) and individual domains, orthostatic intolerance (− 4.6; − 6.3, − 2.9) and gastrointestinal symptoms (− 0.8; − 1.5, − 0.2). Rapid worsening of all study measures was observed with placebo, while patisiran treatment resulted in stable or improved scores compared with baseline. Patisiran demonstrates benefit across a range of burdensome autonomic neuropathy manifestations that deteriorate rapidly without early and continued treatment.
KW - Autonomic nervous system diseases
KW - Hereditary transthyretin-mediated amyloidosis
KW - Patisiran
KW - Polyneuropathy
KW - Small interfering ribonucleic acid (siRNA)
KW - Transthyretin
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U2 - 10.1007/s00415-019-09602-8
DO - 10.1007/s00415-019-09602-8
M3 - Article
C2 - 31728713
AN - SCOPUS:85075260909
VL - 267
SP - 703
EP - 712
JO - Deutsche Zeitschrift fur Nervenheilkunde
JF - Deutsche Zeitschrift fur Nervenheilkunde
SN - 0340-5354
IS - 3
ER -