title: Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia.
abstract: BACKGROUND
  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.).
authors.affiliation: From the Department of Medicine, Université de Montréal and Ecogene-21 Clinical Research Centre, Chicoutimi, QC, Canada (D.G., D.B., K.T.); Isis Pharmaceuticals, Carlsbad (V.J.A., B.F.B., W.S., R.S.G., S.G.H., N.J.V., M.J.G., R.M.C.), and the Department of Medicine, University of California, San Diego, La Jolla (J.L.W.) - both in California; the Department of Medicine, University of Washington, Seattle (J.D.B.); and the Department of Vascular Medicine, Academic Medical Center, Amsterdam (J.J.P.K.).
authors.forename: Daniel
authors.initials: D
authors.lastname: Gaudet
authors.forename: Veronica J
authors.initials: VJ
authors.lastname: Alexander
authors.forename: Brenda F
authors.initials: BF
authors.lastname: Baker
authors.forename: Diane
authors.initials: D
authors.lastname: Brisson
authors.forename: Karine
authors.initials: K
authors.lastname: Tremblay
authors.forename: Walter
authors.initials: W
authors.lastname: Singleton
authors.forename: Richard S
authors.initials: RS
authors.lastname: Geary
authors.forename: Steven G
authors.initials: SG
authors.lastname: Hughes
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Viney
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Graham
authors.forename: Rosanne M
authors.initials: RM
authors.lastname: Crooke
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.forename: John D
authors.initials: JD
authors.lastname: Brunzell
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053305:Apolipoprotein C-III / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D058607:Fibric Acids / Q000627:therapeutic use; D006801:Humans; D015228:Hypertriglyceridemia / Q000097:blood / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009841:Oligonucleotides / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood
chemical_list: D053305:Apolipoprotein C-III; D008076:Cholesterol, HDL; D058607:Fibric Acids; C000593612:ISIS 304801; D009841:Oligonucleotides; D014280:Triglycerides