Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis

被引：1894

作者：

Adams, D. ^{[1
]}

Gonzalez-Duarte, A. ^{[4
]}

O'Riordan, W. D. ^{[5
]}

Yang, C. -C. ^{[6
]}

Ueda, M.

Kristen, A. V. ^{[9
]}

Tournev, I. ^{[11
]}

Schmidt, H. H. ^{[10
]}

Coelho, T. ^{[12
]}

Berk, J. L. ^{[13
]}

Lin, K. -P. ^{[7
]}

Vita, G. ^{[15
]}

Attarian, S. ^{[2
]}

Plante-Bordeneuve, V. ^{[3
]}

Mezei, M. M. ^{[16
,17
]}

Campistol, J. M. ^{[18
]}

Buades, J. ^{[19
,20
]}

Brannagan, T. H., III ^{[21
]}

Kim, B. J. ^{[22
]}

Oh, J. ^{[23
]}

Parman, Y. ^{[24
]}

Sekijima, Y. ^{[8
]}

Hawkins, P. N. ^{[25
]}

Solomon, S. D. ^{[14
]}

Polydefkis, M. ^{[26
]}

Dyck, P. J. ^{[27
]}

Gandhi, P. J. ^{[28
]}

Goyal, S. ^{[28
]}

Chen, J. ^{[28
]}

Strahs, A. L. ^{[28
]}

Nochur, S. V. ^{[28
]}

Sweetser, M. T. ^{[28
]}

Garg, P. P. ^{[28
]}

Vaishnaw, A. K. ^{[28
]}

Gollob, J. A. ^{[28
]}

Suhr, O. B. ^{[29
]}

机构：

[1] Univ Paris Sud, CHU Bicetre, AP HP, INSERM Unite 1195,Natl Reference Ctr Familial Amy, Le Kremlin Bicetre, France

[2] Hop La Timone, Dept Neuromuscular Disorders & ALS, Marseille, France

[3] CHU Henri Mondor, AP HP, Amyloid Network, Dept Neurol, Creteil, France

[4] Natl Inst Med Sci & Nutr Salvador Zubiran, Mexico City, DF, Mexico

[5] eStudySite, Dept Clin Res, San Diego, CA USA

[6] Natl Taiwan Univ Hosp, Dept Neurol, Taipei, Taiwan

[7] Taipei Vet Gen Hosp, Dept Neurol, Taipei, Taiwan

[8] Shinshu Univ, Dept Med Neurol & Rheumatol, Matsumoto, Nagano, Japan

[9] Heidelberg Univ, Dept Cardiol, Heidelberg, Germany

[10] Univ Klinikum Munster, Med Klin B Gastroenterol & Hepatol, Munster, Germany

[11] Univ Multiprofile Hosp Act Treatment, Sofia, Bulgaria

[12] Hosp Santo Antonio, Ctr Hosp Porto, Porto, Portugal

[13] Boston Med Ctr, Dept Med, Amyloidosis Ctr, Boston, MA USA

[14] Harvard Med Sch, Boston, MA USA

[15] Univ Hosp Messina, Dept Clin & Expt Med, Messina, Italy

[16] Vancouver Gen Hosp, Dept Neurol, Vancouver, BC, Canada

[17] Vancouver Gen Hosp, Dept Med, Vancouver, BC, Canada

[18] Hosp Clin Barcelona, Dept Nephrol, Barcelona, Spain

[19] Balear Isl Hlth Res Inst, Palma de Mallorca, Spain

[20] Hosp Son Llatzer, Palma de Mallorca, Spain

[21] Columbia Univ, Dept Neurol, Coll Phys & Surg, New York, NY USA

[22] Sungkyunkwan Univ, Sch Med, Samsung Med Ctr, Seoul, South Korea

[23] Konkuk Univ, Med Ctr, Dept Neurol, Seoul, South Korea

[24] Istanbul Univ, Dept Neurol, Istanbul, Turkey

[25] UCL, Div Med, London, England

[26] Johns Hopkins Bayview Med Ctr Baltimore, Baltimore, MD USA

[27] Mayo Clin, Dept Neurol, Rochester, MN USA

[28] Alnylam Pharmaceut, Cambridge, MA USA

[29] Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2018年 / 379卷 / 01期

关键词：

NATURAL-HISTORY; LATE-ONSET; POLYNEUROPATHY; TAFAMIDIS; SAFETY; PROGRESSION; EFFICACY;

D O I：

10.1056/NEJMoa1716153

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

BACKGROUND Patisiran, an investigational RNA interference therapeutic agent, specifically inhibits hepatic synthesis of transthyretin. METHODS In this phase 3 trial, we randomly assigned patients with hereditary transthyretin amyloidosis with polyneuropathy, in a 2:1 ratio, to receive intravenous patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks. The primary end point was the change from baseline in the modified Neuropathy Impairment Score+7 (mNIS+7; range, 0 to 304, with higher scores indicating more impairment) at 18 months. Other assessments included the Norfolk Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) questionnaire (range, -4 to 136, with higher scores indicating worse quality of life), 10-m walk test (with gait speed measured in meters per second), and modified body-mass index (modified BMI, defined as [weight in kilograms divided by square of height in meters] x albumin level in grams per liter; lower values indicated worse nutritional status). RESULTS A total of 225 patients underwent randomization (148 to the patisiran group and 77 to the placebo group). The mean (+/- SD) mNIS+7 at baseline was 80.9 +/- 41.5 in the patisiran group and 74.6 +/- 37.0 in the placebo group; the least-squares mean (+/- SE) change from baseline was -6.0 +/- 1.7 versus 28.0 +/- 2.6 (difference, -34.0 points; P<0.001) at 18 months. The mean (+/- SD) baseline Norfolk QOL-DN score was 59.6 +/- 28.2 in the patisiran group and 55.5 +/- 24.3 in the placebo group; the least-squares mean (+/- SE) change from baseline was -6.7 +/- 1.8 versus 14.4 +/- 2.7 (difference, -21.1 points; P<0.001) at 18 months. Patisiran also showed an effect on gait speed and modified BMI. At 18 months, the least-squares mean change from baseline in gait speed was 0.08 +/- 0.02 m per second with patisiran versus -0.24 +/- 0.04 m per second with placebo (difference, 0.31 m per second; P<0.001), and the least-squares mean change from baseline in the modified BMI was -3.7 +/- 9.6 versus -119.4 +/- 14.5 (difference, 115.7; P<0.001). Approximately 20% of the patients who received patisiran and 10% of those who received placebo had mild or moderate infusion-related reactions; the overall incidence and types of adverse events were similar in the two groups. CONCLUSIONS In this trial, patisiran improved multiple clinical manifestations of hereditary transthyretin amyloidosis.

引用

页码：11 / 21

页数：11

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