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- 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.
- Authors
Yu, Rosie; Gunawan, Rudy; Li, Zhaoyang; Mittleman, Robert; Mahmood, Asif; Grundy, John; Singleton, Walter; Geary, Richard; Wang, Yanfeng
- Abstract
Purpose: 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 T). 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 C 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.
- Subjects
ANTILIPEMIC agents; APOLIPOPROTEINS; CLINICAL trials; CROSSOVER trials; ELECTROCARDIOGRAPHY; HEART; PLACEBOS; REGRESSION analysis; CHEMICAL inhibitors; PHARMACODYNAMICS
- Publication
European Journal of Clinical Pharmacology, 2016, Vol 72, Issue 3, p267
- ISSN
0031-6970
- Publication type
Article
- DOI
10.1007/s00228-015-1992-y