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Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia.

AbstractBACKGROUND:
Apolipoprotein C-III (APOC3) is a key regulator of plasma triglyceride levels. Elevated triglyceride levels are associated with a risk of adverse cardiovascular events and pancreatitis. ISIS 304801 is a second-generation antisense inhibitor of APOC3 synthesis.
METHODS:
We conducted a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 study to evaluate ISIS 304801 in untreated patients with fasting triglyceride levels between 350 mg per deciliter (4.0 mmol per liter) and 2000 mg per deciliter (22.6 mmol per liter) (ISIS 304801 monotherapy cohort), as well as in patients receiving stable fibrate therapy who had fasting triglyceride levels between 225 mg per deciliter (2.5 mmol per liter) and 2000 mg per deciliter (ISIS 304801-fibrate cohort). Eligible patients were randomly assigned to receive either ISIS 304801, at doses ranging from 100 to 300 mg, or placebo, once weekly for 13 weeks. The primary outcome was the percentage change in APOC3 level from baseline.
RESULTS:
A total of 57 patients were treated in the ISIS 304801 monotherapy cohort (41 received active agent, and 16 received placebo), and 28 patients were treated in the ISIS 304801-fibrate cohort (20 received active agent, and 8 received placebo). The mean (±SD) baseline triglyceride levels in the two cohorts were 581±291 mg per deciliter (6.6±3.3 mmol per liter) and 376±188 mg per deciliter (4.2±2.1 mmol per liter), respectively. Treatment with ISIS 304801 resulted in dose-dependent and prolonged decreases in plasma APOC3 levels when the drug was administered as a single agent (decreases of 40.0±32.0% in the 100-mg group, 63.8±22.3% in the 200-mg group, and 79.6±9.3% in the 300-mg group, vs. an increase of 4.2±41.7% in the placebo group) and when it was administered as an add-on to fibrates (decreases of 60.2±12.5% in the 200-mg group and 70.9±13.0% in the 300-mg group, vs. a decrease of 2.2±25.2% in the placebo group). Concordant reductions of 31.3 to 70.9% were observed in triglyceride levels. No safety concerns were identified in this short-term study.
CONCLUSIONS:
We found that treatment with ISIS 304801 was associated with significant lowering of triglyceride levels, among patients with a broad range of baseline levels, through selective antisense inhibition of APOC3 synthesis. (Funded by Isis Pharmaceuticals; ClinicalTrials.gov number, NCT01529424.).
AuthorsDaniel Gaudet, Veronica J Alexander, Brenda F Baker, Diane Brisson, Karine Tremblay, Walter Singleton, Richard S Geary, Steven G Hughes, Nicholas J Viney, Mark J Graham, Rosanne M Crooke, Joseph L Witztum, John D Brunzell, John J P Kastelein
JournalThe New England journal of medicine (N Engl J Med) Vol. 373 Issue 5 Pg. 438-47 (Jul 30 2015) ISSN: 1533-4406 [Electronic] United States
PMID26222559 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
Chemical References
  • Apolipoprotein C-III
  • Cholesterol, HDL
  • Fibric Acids
  • ISIS 304801
  • Oligonucleotides
  • Triglycerides
Topics
  • Adult
  • Aged
  • Aged, 80 and over
  • Apolipoprotein C-III (antagonists & inhibitors, biosynthesis, blood)
  • Cholesterol, HDL (blood)
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Fibric Acids (therapeutic use)
  • Humans
  • Hypertriglyceridemia (blood, drug therapy)
  • Male
  • Middle Aged
  • Oligonucleotides (administration & dosage, adverse effects, pharmacology)
  • Triglycerides (blood)

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