Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis
Open accessAbstract
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]×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. (Funded by Alnylam Pharmaceuticals; APOLLO ClinicalTrials.gov number, NCT01960348 .).
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Current ATTR amyloidosis treatments are limited by the requirement for long-term administration to maintain TTR knockdown.
“but are limited by the requirement for long-term administration to maintain TTR knockdown.”
From CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis (2021) · cites this paper as [12]
The Trial Design and Regimens section reports patisiran infusions every three weeks for 18 months, and Pharmacodynamics reports sustained TTR reduction during that period. The paper does not establish that long-term administration is required to maintain knockdown after treatment stops, or that this limitation applies to current ATTR treatments generally. (LLM, conf=0.82)
Experimental — accuracy not yet measuredMore extensive TTR knockdown is associated with greater improvement in neuropathic end points in patients with hATTR polyneuropathy.
“More extensive TTR knockdown is associated with greater improvement in neuropathic end points in patients with hATTR polyneuropathy. 12”
From CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis (2021) · cites this paper as [12]
The Primary End Point section reports a correlation between the degree of TTR reduction and change in mNIS+7, a composite neuropathy measure, at 18 months. The paper reports improvements in other end points, but our copy does not link the extent of knockdown to improvement across those end points. (LLM, conf=0.86)
Experimental — accuracy not yet measuredFor liver targets, lipid nanoparticles and N-acetylgalactosamine conjugates are two clinically validated delivery strategies with multiple regulatory approvals.
“For liver targets, lipid nanoparticles (LNPs) and N-acetylgalactosamine (GalNAc) conjugates are two clinically validated delivery strategies, with multiple regulatory approvals that include Onpattro® (patisiran) 2,3 , Givlaari® (givosiran) 4 , Oxlumo® (lumaisran) 5 , and Leqvio® (inclisiran) [6][7][8] , and numerous additional programs in various stages of clinical development across several thera”
From Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates (2022) · cites this paper as [2]
The paper’s introduction describes patisiran as a hepatically directed RNAi therapeutic, and the Results report benefit in a phase 3 trial, supporting its use as a clinical example for a liver target. But our copy calls patisiran investigational and does not identify its delivery system as a lipid nanoparticle or report regulatory approval. The citation is attached to Onpattro (patisiran), not to the other named drugs. (LLM, conf=0.84)
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
The citation lists haven’t been fetched yet
References 25 · Cited by 3,047
Research works printed but not linked: 2
- [5]5. Dungu JN, Anderson LJ, Whelan CJ, Hawkins PN. Cardiac transthyretin amy- loidosis. Heart 2012; 98: 1546-54.
- [23]23. Benson MD, Waddington-Cruz M, Berk JL, et al. Inotersen treatment for pa- tients with hereditary transthyretin amy- loidosis. N Engl J Med 2018; 379:22-31.
- Authors
- Adams, D., Gonzalez-Duarte, A., O’Riordan, W. D., Yang, C.-C., Ueda, M., Kristen, A. V., Tournev, I., Schmidt, H. H., Coelho, T., Berk, J. L., Lin, K.-P., Vita, G., Attarian, S., Planté-Bordeneuve, V., Mezei, M. M., Campistol, J. M., Buades, J., Brannagan, T. H., Kim, B. J., Oh, J., Parman, Y., Sekijima, Y., Hawkins, P. N., Solomon, S. D., Polydefkis, M., Dyck, P. J., Gandhi, P. J., Goyal, S., Chen, J., Strahs, A. L., Nochur, S. V., Sweetser, M. T., Garg, P. P., Vaishnaw, A. K., Gollob, J. A., & Suhr, O. B.
- Affiliations
- Université Paris-Sud (FR)
- From Assistance Publique–Hôpitaux de Paris (APHP), National Reference Center for Familial Amyloidotic Polyneuropathy, Centre Hospitalier Universitaire (CHU) Bicêtre, INSERM Unité 1195, Université Paris-Sud, Le Kremlin-Bicêtre (D.A.), the Department of Neuromuscular Disorders and ALS, Hôpital de la Timone, Marseille (S.A.), and the Department of Neurology, Amyloid Network, CHU Henri Mondor–APHP, Créteil (V.P.-B.) — all in France; the National Institute of Medical Sciences and Nutrition–Salvador...
- ORCID
- Yang, Chih-Chao
- Ueda, Mitsuharu
- Kristen, Arnt V.
- Tournev, Ivailo
- Schmidt, Hartmut H.
- Coelho, Teresa
- Berk, John L.
- Vita, Giuseppe
- Attarian, Shahram
- Mezei, Michelle M.
- Campistol, Josep M.
- Buades, Juan
- Brannagan, Thomas H.
- Oh, Jeeyoung
- Sekijima, Yoshiki
- Hawkins, Philip N.
- Solomon, Scott D.
- Polydefkis, Michael
- Dyck, Peter J.
- Chen, Jihong
- Strahs, Andrew L.
- Gollob, Jared A.
- Suhr, Ole B.
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2018-07-05
- Volume
- 379
- Issue
- 1
- Pages
- 11-21
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2810909862
- Cited by
- 3,047
- References
- 25
- Citations by year
- 2026: 351 · 2025: 427 · 2024: 375 · 2023: 349 · 2022: 402 · 2021: 361 · 2020: 395 · 2019: 325 · 2018: 59
- FWCI
- 101.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- RECERCAT (Consorci de Serveis Universitaris de Catalunya) (publishedVersion)
- Dipòsit Digital de la Universitat de Barcelona (Universitat de Barcelona) (submittedVersion, public-domain)
- Docusalut (Conselleria de Salut i Consum del Govern de les Illes Balears) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Funders
- Alnylam Pharmaceuticals (Not applicable)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Amyloidosis: Diagnosis, Treatment, Outcomes
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- patisiran, hereditary transthyretin amyloidosis, prealbumin, RNA interference, polyneuropathy, quality of life, walking speed, nutritional status, body mass index, intravenous administration, adverse events
- MeSH terms
- RNAi Therapeutics, Walk Test, Adult, Aged, Aged, 80 and over, Double-Blind Method, Edema, Female, Humans, Infusions, Intravenous, Male, Middle Aged, Polyneuropathies, Prealbumin, Quality of Life, Severity of Illness Index, Least-Squares Analysis, Disease Progression, Gait Disorders, Neurologic, Amyloid Neuropathies, Familial, RNA, Small Interfering, Administration, Intravenous
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
