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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

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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 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.

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Acknowledgements

The authors wish to thank Drs. Brenda Baker, Shariq Ali, Samirita de Banerjee, Barbara Pizza, Charlotte Sensinger, Steve Hughes, JoAnn Flaim, Teresa Brandt, Dan Norris, and Ken Luu, and Scott Henry for their scientific discussion and critical review of the manuscript. Finally, this manuscript would not be possible without the administrative support provided by Robert Saunders, for which we are grateful.

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Authors and Affiliations

  1. Isis Pharmaceuticals, Inc., 2855 Gazelle Court, Carlsbad, CA, 92010, USA

    Rosie Z. Yu, Rudy Gunawan, John S. Grundy, Walter Singleton, Richard Geary & Yanfeng Wang

  2. Genzyme, A Sanofi Company, Cambridge, MA, USA

    Zhaoyang Li, Robert S. Mittleman & Asif Mahmood

Authors
  1. Rosie Z. Yu
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  2. Rudy Gunawan
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  3. Zhaoyang Li
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  4. Robert S. Mittleman
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  6. John S. Grundy
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  7. Walter Singleton
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  8. Richard Geary
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  9. Yanfeng Wang
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Corresponding author

Correspondence to Rosie Z. Yu.

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Conflicts of interest

The authors are either employed by Isis Pharmaceuticals, Inc. or Genzyme, A Sanofi Company, developers and marketers of mipomersen.

Additional information

The author, John S. Grundy, is no longer employed by Isis Pharmaceuticals, Inc., Carlsbad, California, USA.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplement Table S1

Time Averaged Outlier Analysis of All Subjects in the Phase I Dose Escalation Study. (DOC 56 kb)

Supplement Table S2

Summary of Demographics and Baseline Characteristics of the tQT Study. (DOC 58 kb)

Supplement Table S3

Time Averaged Outlier Analysis of All Subjects in the tQT Study. (DOC 48 kb)

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Yu, R.Z., Gunawan, R., Li, Z. et al. 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. Eur J Clin Pharmacol 72, 267–275 (2016). https://doi.org/10.1007/s00228-015-1992-y

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  • DOI: https://doi.org/10.1007/s00228-015-1992-y

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