title: Results of a proof of concept, double-blind, randomized trial of a second generation antisense oligonucleotide targeting high-sensitivity C-reactive protein (hs-CRP) in rheumatoid arthritis.
abstract: BACKGROUND
  This randomized, double-blind, phase II study evaluated the pharmacodynamics, safety and tolerability of ISIS 329993 (ISIS-CRPRx), an antisense oligonucleotide, in patients with active rheumatoid arthritis (RA).
  
  
  METHODS
  Patients with active RA of at least six months duration were randomized into three cohorts to receive ISIS-CRPRx (100 mg, 200 mg or 400 mg) or placebo (3 active:1 placebo within each cohort) via subcutaneous (SC) injection on Days 1, 3, 5 and 8 and then once weekly for the next 11 weeks. The effects of study treatment on high-sensitivity C-reactive protein (hs-CRP) level were evaluated. An exploratory analysis on disease activity was assessed via the American College of Rheumatology 20% improvement criteria (ACR20). Safety was evaluated via adverse events and laboratory measures.
  
  
  RESULTS
  Fifty-one patients received one of the following treatments: ISIS-CRPRx 100 mg, n = 12; 200 mg, n = 13, 400 mg, n = 14; placebo n = 12. In the ISIS-CRPRx treatment groups there were dose-dependent reductions in hs-CRP. At Day 36 the mean percent change from baseline was: placebo: -14.4%; ISIS-CRPRx 100 mg: -19.5%; 200 mg: -56.6% and 400 mg: -76.7%, (P = 0.0015 placebo compared to 400 mg). There were no differences between treatment groups and placebo in the ACR20 at Day 36 or Day 92. There were no serious infections and no elevations in liver function tests, lipids, creatinine or other lab abnormalities related to ISIS-CRPRx.
  
  
  CONCLUSIONS
  In this study, ISIS-CRPRx selectively reduced hs-CRP in a dose-dependent manner, and was well-tolerated in patients with RA. Its utility as a therapy in RA remains unclear.
  
  
  BACKGROUND
  Clinicaltrials.gov NCT01414101 . Registered 21 July 2011.
authors.affiliation: Isis Pharmaceuticals, Inc, 2855 Gazelle Court, Carlsbad, CA, 92010, USA. mswarrenmd47@yahoo.com.
authors.forename: Marshelle S
authors.initials: MS
authors.lastname: Warren
authors.affiliation: Isis Pharmaceuticals, Inc, 2855 Gazelle Court, Carlsbad, CA, 92010, USA. shughes@isisph.com.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Hughes
authors.affiliation: Isis Pharmaceuticals, Inc, 2855 Gazelle Court, Carlsbad, CA, 92010, USA. wsingleton@isisph.com.
authors.forename: Walter
authors.initials: W
authors.lastname: Singleton
authors.affiliation: Isis Pharmaceuticals, Inc, 2855 Gazelle Court, Carlsbad, CA, 92010, USA. myamashita@isisph.com.
authors.forename: Mason
authors.initials: M
authors.lastname: Yamashita
authors.affiliation: Stanford University, 1000 Welch Rd Palo, Alto, CA, 94304, USA. genovese@stanford.edu.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Genovese
mesh_terms: D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy*; D002097:C-Reactive Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D006801:Humans; D038622:Internationality; D008297:Male; D008875:Middle Aged; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage*
chemical_list: D016376:Oligonucleotides, Antisense; D002097:C-Reactive Protein