title: No effect on QT intervals of mipomersen, a 2'-O-methoxyethyl modified antisense oligonucleotide targeting ApoB-100 mRNA, in a phase I dose escalation placebo-controlled study, and confirmed by a thorough QT (tQT) study, in healthy subjects.
abstract: OBJECTIVE
  The aim of this study to evaluate the effect of mipomersen on QT intervals in a phase I dose escalation, placebo-controlled study, and a thorough QT (tQT) study in healthy subjects.
  
  
  METHODS
  In the initial phase I study, 29 healthy subjects received either single or multiple (for 4 weeks) ascending doses of mipomersen (50-400 mg) administered subcutaneously (SC) or via a 2-h intravenous (IV) infusion, and 7 subjects received placebo. In the confirmative tQT study, 58 healthy subjects received placebo, 400 mg IV moxifloxacin, 200 mg SC, or 200 mg IV of mipomersen in a double-blind, 4-way crossover design with a minimum 5-day washout between treatments. ECG measurements were performed at baseline and selected time points (including Tmax). The correlation between QTcF intervals corrected for baseline and time-matched placebo when available with PK plasma exposure was evaluated by linear regression analysis.
  
  
  RESULTS
  In the phase I study, no positive correlation between the PK exposure and ∆QTcF or ∆∆QTcF was observed within the wide dose or exposure range tested. Similar results were observed in the tQT study, where the predicted ΔΔQTcF and its upper bound of the 90% CI at Cmax of therapeutic and supratherapeutic dose were approximately -1.7 and 2.9 ms, respectively.
  
  
  CONCLUSIONS
  Mipomersen showed no effect on QT intervals in both the phase I dose escalation study and the tQT study. These results support the proposal that QT assessment can be made in a phase I dose escalation study, and no tQT study may be necessary if the phase I dose escalation study showed a negative QT effect.
authors.affiliation: Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA, 92010, USA. ryu@isisph.com.
authors.forename: Rosie Z
authors.initials: RZ
authors.lastname: Yu
authors.affiliation: Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA, 92010, USA.
authors.forename: Rudy
authors.initials: R
authors.lastname: Gunawan
authors.affiliation: Genzyme, A Sanofi Company, Cambridge, MA, USA.
authors.forename: Zhaoyang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Genzyme, A Sanofi Company, Cambridge, MA, USA.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Mittleman
authors.affiliation: Genzyme, A Sanofi Company, Cambridge, MA, USA.
authors.forename: Asif
authors.initials: A
authors.lastname: Mahmood
authors.affiliation: Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA, 92010, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Grundy
authors.affiliation: Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA, 92010, USA.
authors.forename: Walter
authors.initials: W
authors.lastname: Singleton
authors.affiliation: Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA, 92010, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Geary
authors.affiliation: Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA, 92010, USA.
authors.forename: Yanfeng
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000328:Adult; D053299:Apolipoprotein B-100 / Q000235:genetics; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D020319:Oligodeoxyribonucleotides, Antisense / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D009841:Oligonucleotides / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D012333:RNA, Messenger; D055815:Young Adult
chemical_list: D053299:Apolipoprotein B-100; D020319:Oligodeoxyribonucleotides, Antisense; D009841:Oligonucleotides; D012333:RNA, Messenger; C524142:mipomersen
keywords: Antisense oligonucleotide; Mipomersen; Phase I study; QT; tQT