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

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

来源：European Journal of Endocrinology, 2018, 179(2): 97-108.

DOI：10.1530/EJE-18-0138

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 200 mg 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 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.

• 出版日期2018-8