A randomised, open-label, parallel group phase 2 study of antisense oligonucleotide therapy in acromegaly
Trainer, Peter J. (Department of Endocrinology)
Newell-Price, John D. C. (Royal Hallamshire Hospital)
Ayuk, John (Medicine Endocrinology)
Aylwin, Simon J. B. (King's College Hospital NHS Foundation Trust)
Rees, Aled (Neuroscience and Mental Health Research Institute)
Drake, William (Department of Endocrinology)
Chanson, Philippe (Inserm 1185)
Brue, Thierry (APHM)
Webb, S. M 1952- (Institut d'Investigació Biomèdica Sant Pau)
Fajardo, Carmen (Servicio de Endocrinología)
Aller, Javier (Endocrinology Department)
McCormack, Ann I (Garvan Institute of Medical Research and St Vincent's Hospital)
Torpy, David J. (Royal Adelaide Hospital)
Tachas, George (Antisense Therapeutics Limited)
Atley, Lynne (Antisense Therapeutics Limited)
Ryder, David (Manchester Academic Health Science Centre (MAHSC) Clinical Trials Unit)
Bidlingmaier, Martin (Endocrine Laboratory)
Universitat Autònoma de Barcelona

Fecha:	2018
Resumen:	ATL1103 is a second-generation antisense oligomer targeting the human growth hormone (GH) receptor. This phase 2 randomised, open-label, parallel-group study assessed the potential of ATL1103 as a treatment for acromegaly. Twenty-six patients with active acromegaly (IGF-I >130% upper limit of normal) were randomised to subcutaneous ATL1103 200 mg either once or twice weekly for 13 weeks and monitored for a further 8-week washout period. The primary efficacy measures were change in IGF-I at week 14, compared to baseline and between cohorts. For secondary endpoints (IGFBP3, acid labile subunit (ALS), GH, growth hormone-binding protein (GHBP)), comparison was between baseline and week 14. Safety was assessed by reported adverse events. Baseline median IGF-I was 447 and 649 ng/mL in the once- and twice-weekly groups respectively. Compared to baseline, at week 14, twice-weekly ATL1103 resulted in a median fall in IGF-I of 27. 8% (P = 0. 0002). Between cohort comparison at week 14 demonstrated the median fall in IGF-I to be 25. 8% (P = 0. 0012) greater with twice-weekly dosing. In the twice-weekly cohort, IGF-I was still declining at week 14, and remained lower at week 21 than at baseline by a median of 18. 7% (P = 0. 0005). Compared to baseline, by week 14, IGFBP3 and ALS had declined by a median of 8. 9% (P = 0. 027) and 16. 7% (P = 0. 017) with twice-weekly ATL1103; GH had increased by a median of 46% at week 14 (P = 0. 001). IGFBP3, ALS and GH did not change with weekly ATL1103. GHBP fell by a median of 23. 6% and 48. 8% in the once- and twice-weekly cohorts (P = 0. 027 and P = 0. 005) respectively. ATL1103 was well tolerated, although 84. 6% of patients experienced mild-to-moderate injection-site reactions. This study provides proof of concept that ATL1103 is able to significantly lower IGF-I in patients with acromegaly.
Nota:	Altres ajuts: The study was funded by Antisense Therapeutics Limited (Melbourne, Australia).
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Publicado en:	European journal of endocrinology, Vol. 179 (may 2018) , p. 97-108, ISSN 1479-683X

DOI: 10.1530/EJE-18-0138
PMID: 29789410

12 p, 755.8 KB

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