A randomised, open-label, parallel group phase 2 study of antisense oligonucleotide therapy in acromegaly

Peter J. Trainer, John D.C. Newell-Price, John Ayuk, Simon J.B. Aylwin, Aled Rees, William Drake, Philippe Chanson, Thierry Brue, Susan M. Webb, Carmen Fajardo, Javier Aller, Ann I. McCormack, David J. Torpy, George Tachas, Lynne Atley, David Ryder, Martin Bidlingmaier

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23 Citations (Scopus)


© 2018 The authors. Objective: 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. Design: Twenty-six patients with active acromegaly (IGF-I >130% upper limit of normal) were randomised to subcutaneous ATL1103 200mg either once or twice weekly for 13 weeks and monitored for a further 8-week washout period. Methods: 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. Results and conclusions: Baseline median IGF-I was 447 and 649ng/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.
Original languageEnglish
Pages (from-to)97-108
JournalEuropean Journal of Endocrinology
Issue number2
Publication statusPublished - 1 Aug 2018


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