Evidence map›Paper›PMID 28538111›Full record

Trial reportThe New England journal of medicine2017

Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides.

Mark J Graham, Richard G Lee, Teresa A Brandt, Li-Jung Tai, Wuxia Fu, Raechel Peralta, Rosie Yu, Eunju Hurh, Erika Paz, Bradley W McEvoy and 8 more

Registry-linked trialOpen access · bronzeAbstract readClinical Trial, Phase IRandomized Controlled Trial
PubMed Publisher
In one paragraph

Trial report in The New England journal of medicine, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02709850 (A Placebo-Controlled, Dose-Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of ISIS 703802, Targeting ANGPTL3, Administered Subcutaneously to Healthy Volunteers With Elevated Triglycerides and Subjects With Familial Hypercholesterolemia), which is not on this map. Cited by 294 papers, 4 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
294citing papers in PubMed, 4 pooled it
44.6field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT02709850 phase1completednot on this map

A Placebo-Controlled, Dose-Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single and Multiple Doses of ISIS 703802, Targeting ANGPTL3, Administered Subcutaneously to Healthy Volunteers With Elevated Triglycerides and Subjects With Familial Hypercholesterolemia

TypeinterventionalSponsorIonis Pharmaceuticals, Inc.Ran2015 to 2017Enrolled48ConditionsHypertriglyceridemia, Familial HypercholesterolemiaArmsIONIS ANGPTL3-LRx, Placebo
3 · Its place in the literature

Who cites it

294 citing papers in PubMed, 4 syntheses or guidelines pooled it, 574 citations in OpenAlex.

  1. Pooled it
  2. Pooled it
  3. The promising novel therapies for familial hypercholesterolemia.Journal of clinical laboratory analysis · 2022
    Pooled it
  4. Biotechnology Approaches for the Treatment of Dyslipidemia.Cardiovascular drugs and therapy · 2021
    Pooled it
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  11. Integrated Assessment of Phase 2 Data on GalNAcNucleic acid therapeutics · 2023
    Trial
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  15. Identifying the Lipidomic Effects of a Rare Loss-of-Function Deletion inCirculation. Genomic and precision medicine · 2021
    Trial
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  18. Review
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  20. Genetic factors contributing to atherosclerosis.Current opinion in cardiology · 2026
    Review

234 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

18 authors at 3 institutions in 1 country.

Mark J GrahamFrom Ionis Pharmaceuticals, Carlsbad (M.J.G., R.G.L., T.A.B., L.-J.T., W.F., R.P., R.Y., E.P., B.W.M., B.F.B., N.C.P., S.G.H., R.S.G., R.M.C., S.T.), and the University of California, San Diego, La Jolla (J.L.W., S.T.) - both in California; and Akcea Therapeutics, Cambridge, MA (E.H., A.D.).
Richard G LeeFrom Ionis Pharmaceuticals, Carlsbad (M.J.G., R.G.L., T.A.B., L.-J.T., W.F., R.P., R.Y., E.P., B.W.M., B.F.B., N.C.P., S.G.H., R.S.G., R.M.C., S.T.), and the University of California, San Diego, La Jolla (J.L.W., S.T.) - both in California; and Akcea Therapeutics, Cambridge, MA (E.H., A.D.).
Teresa A BrandtFrom Ionis Pharmaceuticals, Carlsbad (M.J.G., R.G.L., T.A.B., L.-J.T., W.F., R.P., R.Y., E.P., B.W.M., B.F.B., N.C.P., S.G.H., R.S.G., R.M.C., S.T.), and the University of California, San Diego, La Jolla (J.L.W., S.T.) - both in California; and Akcea Therapeutics, Cambridge, MA (E.H., A.D.).
Li-Jung TaiFrom Ionis Pharmaceuticals, Carlsbad (M.J.G., R.G.L., T.A.B., L.-J.T., W.F., R.P., R.Y., E.P., B.W.M., B.F.B., N.C.P., S.G.H., R.S.G., R.M.C., S.T.), and the University of California, San Diego, La Jolla (J.L.W., S.T.) - both in California; and Akcea Therapeutics, Cambridge, MA (E.H., A.D.).
Wuxia FuFrom Ionis Pharmaceuticals, Carlsbad (M.J.G., R.G.L., T.A.B., L.-J.T., W.F., R.P., R.Y., E.P., B.W.M., B.F.B., N.C.P., S.G.H., R.S.G., R.M.C., S.T.), and the University of California, San Diego, La Jolla (J.L.W., S.T.) - both in California; and Akcea Therapeutics, Cambridge, MA (E.H., A.D.).
Raechel PeraltaFrom Ionis Pharmaceuticals, Carlsbad (M.J.G., R.G.L., T.A.B., L.-J.T., W.F., R.P., R.Y., E.P., B.W.M., B.F.B., N.C.P., S.G.H., R.S.G., R.M.C., S.T.), and the University of California, San Diego, La Jolla (J.L.W., S.T.) - both in California; and Akcea Therapeutics, Cambridge, MA (E.H., A.D.).
Rosie YuFrom Ionis Pharmaceuticals, Carlsbad (M.J.G., R.G.L., T.A.B., L.-J.T., W.F., R.P., R.Y., E.P., B.W.M., B.F.B., N.C.P., S.G.H., R.S.G., R.M.C., S.T.), and the University of California, San Diego, La Jolla (J.L.W., S.T.) - both in California; and Akcea Therapeutics, Cambridge, MA (E.H., A.D.).
Eunju HurhFrom Ionis Pharmaceuticals, Carlsbad (M.J.G., R.G.L., T.A.B., L.-J.T., W.F., R.P., R.Y., E.P., B.W.M., B.F.B., N.C.P., S.G.H., R.S.G., R.M.C., S.T.), and the University of California, San Diego, La Jolla (J.L.W., S.T.) - both in California; and Akcea Therapeutics, Cambridge, MA (E.H., A.D.).
Erika PazFrom Ionis Pharmaceuticals, Carlsbad (M.J.G., R.G.L., T.A.B., L.-J.T., W.F., R.P., R.Y., E.P., B.W.M., B.F.B., N.C.P., S.G.H., R.S.G., R.M.C., S.T.), and the University of California, San Diego, La Jolla (J.L.W., S.T.) - both in California; and Akcea Therapeutics, Cambridge, MA (E.H., A.D.).
Bradley W McEvoyFrom Ionis Pharmaceuticals, Carlsbad (M.J.G., R.G.L., T.A.B., L.-J.T., W.F., R.P., R.Y., E.P., B.W.M., B.F.B., N.C.P., S.G.H., R.S.G., R.M.C., S.T.), and the University of California, San Diego, La Jolla (J.L.W., S.T.) - both in California; and Akcea Therapeutics, Cambridge, MA (E.H., A.D.).
Brenda F BakerFrom Ionis Pharmaceuticals, Carlsbad (M.J.G., R.G.L., T.A.B., L.-J.T., W.F., R.P., R.Y., E.P., B.W.M., B.F.B., N.C.P., S.G.H., R.S.G., R.M.C., S.T.), and the University of California, San Diego, La Jolla (J.L.W., S.T.) - both in California; and Akcea Therapeutics, Cambridge, MA (E.H., A.D.).
Nguyen C PhamFrom Ionis Pharmaceuticals, Carlsbad (M.J.G., R.G.L., T.A.B., L.-J.T., W.F., R.P., R.Y., E.P., B.W.M., B.F.B., N.C.P., S.G.H., R.S.G., R.M.C., S.T.), and the University of California, San Diego, La Jolla (J.L.W., S.T.) - both in California; and Akcea Therapeutics, Cambridge, MA (E.H., A.D.).
Andres DigenioFrom Ionis Pharmaceuticals, Carlsbad (M.J.G., R.G.L., T.A.B., L.-J.T., W.F., R.P., R.Y., E.P., B.W.M., B.F.B., N.C.P., S.G.H., R.S.G., R.M.C., S.T.), and the University of California, San Diego, La Jolla (J.L.W., S.T.) - both in California; and Akcea Therapeutics, Cambridge, MA (E.H., A.D.).
Steven G HughesFrom Ionis Pharmaceuticals, Carlsbad (M.J.G., R.G.L., T.A.B., L.-J.T., W.F., R.P., R.Y., E.P., B.W.M., B.F.B., N.C.P., S.G.H., R.S.G., R.M.C., S.T.), and the University of California, San Diego, La Jolla (J.L.W., S.T.) - both in California; and Akcea Therapeutics, Cambridge, MA (E.H., A.D.).
Richard S GearyFrom Ionis Pharmaceuticals, Carlsbad (M.J.G., R.G.L., T.A.B., L.-J.T., W.F., R.P., R.Y., E.P., B.W.M., B.F.B., N.C.P., S.G.H., R.S.G., R.M.C., S.T.), and the University of California, San Diego, La Jolla (J.L.W., S.T.) - both in California; and Akcea Therapeutics, Cambridge, MA (E.H., A.D.).
Joseph L WitztumFrom Ionis Pharmaceuticals, Carlsbad (M.J.G., R.G.L., T.A.B., L.-J.T., W.F., R.P., R.Y., E.P., B.W.M., B.F.B., N.C.P., S.G.H., R.S.G., R.M.C., S.T.), and the University of California, San Diego, La Jolla (J.L.W., S.T.) - both in California; and Akcea Therapeutics, Cambridge, MA (E.H., A.D.).
Rosanne M CrookeFrom Ionis Pharmaceuticals, Carlsbad (M.J.G., R.G.L., T.A.B., L.-J.T., W.F., R.P., R.Y., E.P., B.W.M., B.F.B., N.C.P., S.G.H., R.S.G., R.M.C., S.T.), and the University of California, San Diego, La Jolla (J.L.W., S.T.) - both in California; and Akcea Therapeutics, Cambridge, MA (E.H., A.D.).
Sotirios TsimikasFrom Ionis Pharmaceuticals, Carlsbad (M.J.G., R.G.L., T.A.B., L.-J.T., W.F., R.P., R.Y., E.P., B.W.M., B.F.B., N.C.P., S.G.H., R.S.G., R.M.C., S.T.), and the University of California, San Diego, La Jolla (J.L.W., S.T.) - both in California; and Akcea Therapeutics, Cambridge, MA (E.H., A.D.).
Ionis Pharmaceuticals (United States) · USAkebia Therapeutics (United States) · USUniversity of California, San Diego · US

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundEpidemiologic and genomewide association studies have linked loss-of-function variants in ANGPTL3, encoding angiopoietin-like 3, with low levels of plasma lipoproteins.

methodsWe evaluated antisense oligonucleotides (ASOs) targeting Angptl3 messenger RNA (mRNA) for effects on plasma lipid levels, triglyceride clearance, liver triglyceride content, insulin sensitivity, and atherosclerosis in mice. Subsequently, 44 human participants (with triglyceride levels of either 90 to 150 mg per deciliter [1.0 to 1.7 mmol per liter] or >150 mg per deciliter, depending on the dose group) were randomly assigned to receive subcutaneous injections of placebo or an antisense oligonucleotide targeting ANGPTL3 mRNA in a single dose (20, 40, or 80 mg) or multiple doses (10, 20, 40, or 60 mg per week for 6 weeks). The main end points were safety, side-effect profile, pharmacokinetic and pharmacodynamic measures, and changes in levels of lipids and lipoproteins.

resultsThe treated mice had dose-dependent reductions in levels of hepatic Angptl3 mRNA, Angptl3 protein, triglycerides, and low-density lipoprotein (LDL) cholesterol, as well as reductions in liver triglyceride content and atherosclerosis progression and increases in insulin sensitivity. After 6 weeks of treatment, persons in the multiple-dose groups had reductions in levels of ANGPTL3 protein (reductions of 46.6 to 84.5% from baseline, P<0.01 for all doses vs. placebo) and in levels of triglycerides (reductions of 33.2 to 63.1%), LDL cholesterol (1.3 to 32.9%), very-low-density lipoprotein cholesterol (27.9 to 60.0%), non-high-density lipoprotein cholesterol (10.0 to 36.6%), apolipoprotein B (3.4 to 25.7%), and apolipoprotein C-III (18.9 to 58.8%). Three participants who received the antisense oligonucleotide and three who received placebo reported dizziness or headache. There were no serious adverse events.

conclusionsOligonucleotides targeting mouse Angptl3 retarded the progression of atherosclerosis and reduced levels of atherogenic lipoproteins in mice. Use of the same strategy to target human ANGPTL3 reduced levels of atherogenic lipoproteins in humans. (Funded by Ionis Pharmaceuticals; ClinicalTrials.gov number, NCT02709850 .).

Indexed as

AdultAgedAngiopoietin-Like Protein 3Angiopoietin-like ProteinsAngiopoietinsAnimalsAtherosclerosisCoronary Artery DiseaseDisease Models, AnimalDouble-Blind MethodDyslipidemiasFemaleHumansLipid MetabolismLipidsMaleAngiopoietin-Like Protein 3Angiopoietin-like ProteinsAngiopoietinsANGPTL3 protein, humanAngptl3 protein, mouseIONIS-ANGPTL3-LRxLipidsOligonucleotidesOligonucleotides, AntisenseRNA, Messenger

Identifiers

PMID28538111
OpenAlexW2618984243

What OpenQuestion holds

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Read underepoch 390

Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.