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European Journal of Pediatrics

, Volume 178, Issue 2, pp 253–258 | Cite as

Injection site reactions after long-term subcutaneous delivery of drisapersen: a retrospective study

  • Niels HilhorstEmail author
  • Ifigenia Spanoudi-Kitrimi
  • Nathalie Goemans
  • Marie-Anne Morren
Original Article

Abstract

A retrospective study in which we reviewed the hospital files of a subset of 7 patients with Duchenne muscular dystrophy participating in the open-label phase I/II PRO051-02 study in Leuven. The objective of this study was to describe in detail the injection site reactions in these children treated with drisapersen (PRO-051), a 2′-O-methyl phosphorothioate RNA antisense oligonucleotide, that induces exon 51 skipping in Duchenne muscular dystrophy. Antisense oligonucleotides, restoring the reading frame by skipping of exons, have become a potential treatment of Duchenne muscular dystrophy and other monogenetic diseases. Erythema followed by hyperpigmentation, fibrosis, and calcification were seen at the injection sites in all children. Ulcerations, which were difficult to heal, occurred in 5 of 7 children. Progression still occurred after switching to intravenous administration of drisapersen or even after stopping therapy. Systemic reactions included a reversible proteinuria and α1-microglobulinuria. Moreover, hypotrichosis was a common feature.

Conclusion: Subcutaneous administration of drisapersen causes severe and progressive injection site effects.

What is known:

• Antisense oligonucleotides offer the possibility to convert Duchenne muscular dystrophy to the less severe Becker type. This can potentially be achieved by targeting and skipping specific exons of the Duchenne muscular dystrophy gene to restore the disrupted reading frame and to induce the production of a semi functional dystrophin protein.

• Drisapersen is such an antisense oligonucleotides which can be administered subcutaneously. Its use has been tested extensively in the escalating dose pilot study (PRO051-02).

What is new:

• This report describes the injection site reactions caused by this type of agent in detail which has never been done before. We therefore reviewed the hospital files of 7 patients with Duchenne muscular dystrophy participating in the phase I/II open-label, escalating dose pilot study (PRO051-02) with drisapersen.

• Severe side effects starting with erythema, hyperpigmentation, and later fibrosis, calcification, and difficult to treat ulcerations developed in all patients, and these continued to progress even after cessation of drisapersen. We discuss some possible underlying mechanisms. The exact mechanism however is still not known.

Keywords

Duchenne muscular dystrophy Antisense oligonucleotides Drisapersen (PRO-051) Injection site reactions 

Abbreviations

2OMePS

2′-O-methyl phosphorothioate

AON

Antisense oligonucleotide

DMD

Duchenne muscular dystrophy

ISR

Injection site reactions

LNA-PS

Locked nucleic acid-phosphorothioate

MOE-PS

Methoxyethyl-phosphorothioate

PS

Phosphorothioate

Notes

Acknowledgments

We thank Petra De Haes for comments that greatly improved the manuscript. We would also like to thank the BioMarin Pharmaceutical Inc. for disclosing all information regarding drisapersen.

Portions of this study have been presented at the annual European Society for Pediatric Dermatology (ESPD) congress in Palma de Mallorca on October the 21st 2017.

Authors’ contribution

N.H. (leading author), N.G. and MA.M. (senior author) collected and analyzed the data. N.H. and MA.M drafted the manuscript and designed the figures. N.G. contributed to the writing of the manuscript. I.S. analyzed portions of the data and made corrections in the tables of the final version. All authors revised the final version of the article before submitting it.

Compliance with ethical standards

Conflict of interest

Nathalie Goemans was principle investigator for PRO051. However, no potential conflicts of interest were reported by the authors.

Informed consent

All subjects have given their consent to use their data from the PRO051 study for further research and articles.

Supplementary material

431_2018_3272_MOESM1_ESM.docx (31 kb)
Supplementary Table 1 (DOCX 31 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Niels Hilhorst
    • 1
    Email author
  • Ifigenia Spanoudi-Kitrimi
    • 1
  • Nathalie Goemans
    • 2
  • Marie-Anne Morren
    • 1
  1. 1.Department of DermatologyUZ Leuven Campus GasthuisbergLeuvenBelgium
  2. 2.Department of PediatricsUZ Leuven Campus GasthuisbergLeuvenBelgium

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